Intraocular implant delivery apparatus and methods of use thereof

ABSTRACT

Apparatus and methods for introducing a solid or semi-solid intraocular drug-containing implant into the anterior chamber of an eye are described. The drug-containing implant can be a rod-shaped biodegradable implant that may provide for the extended release of the drug and may be effective for treating a medical condition of the eye. The apparatus is ergonomically designed in the shape or style of a pen with tactile surfaces for easy gripping, a needle-rotation knob to permit orientation of the needle bevel in relation to the eye, and a spring-actuated mechanism for consistent deployment of the implant.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/002,078 filed Aug. 25, 2020, which is a continuation of U.S. patentapplication Ser. No. 14/632,783, filed Feb. 26, 2015, now U.S. patentSer. No. 10/780,218, which claims the benefit of U.S. Provisional PatentApplication No. 61/944,840, filed Feb. 26, 2014, the disclosures ofwhich are hereby incorporated by reference in their entireties and serveas the basis of a priority and/or benefit claim for the presentapplication.

FIELD

The present invention relates to methods and apparatus for introducing asolid or semi-solid intraocular drug-containing implant into theanterior chamber of an eye to thereby treat an ocular condition, such asocular hypertension or glaucoma.

BACKGROUND

Extended-release drug delivery systems in the form of biodegradableintraocular implants, such as extruded implants, can provide aneffective means for delivering therapeutically effective levels of adrug to the eye of patient suffering from an ocular condition. Varioussites exist in the eye for implantation of a drug delivery system,including the vitreous, anterior and posterior chambers, as well as theintraretinal, subretinal, intrachoroidal, suprachoroidal, intrascleral,episcleral, subconjunctival, subtenon, intracorneal and epicornealspaces. The particular site chosen for the drug implant may depend onthe ocular condition and the region of the eye affected by thecondition, and/or on the drug to be delivered. An ocular region ofparticular interest in some patients, such as those suffering fromglaucoma and/or ocular hypertension, is the fluid-filled space in theeye known as the anterior chamber. Located between the iris and theinnermost corneal surface or corneal endothelium, the anterior chambercontains structures such as the trabecular meshwork that regulate thedrainage of aqueous humor. The balanced flow of aqueous humor from theciliary processes in the posterior chamber, where it is produced,through the anterior chamber is essential for normal maintenance ofintraocular pressure (TOP) in the eye.

Physical or biochemical factors that impair drainage of aqueous humorfrom the anterior chamber of the eye may lead to elevated intraocularpressure, or ocular hypertension, which may increase the risk fordeveloping glaucoma. Therefore, a clinical goal in the treatment ofglaucoma can be to reduce intraocular pressure. Conventional treatmentsfor the reduction of IOP typically involve topical application of anIOP-lowering drug, which may act on tissues in the anterior chamber ofthe eye to promote the drainage of aqueous humor. Biodegradable,sustained-release drug delivery systems that can continuously deliver atherapeutically effective amount of an anti-hypertensive drug into theanterior chamber of the eye may be a useful and welcome alternative forsome patients that rely on the regular daily instillation of ocularanti-hypertensives or other anti-glaucoma medications to controlintraocular pressure and manage symptoms associated with glaucoma.

Intraocular drug delivery systems in the form of extruded implants forthe sustained delivery of an IOP-lowering drug to the eye and methodsand apparatus for administering a biodegradable drug delivery systeminto the vitreous body of an eye have been described. See, for example,U.S. Pat. No. 7,799,336, describing biocompatible intraocular implantscontaining a prostamide component and a biodegradable polymer fortreating an ocular condition such as glaucoma, and U.S. Pat. No.6,899,717, describing methods and apparatus for delivering bioerodibleimplants into various locations within the eye, particularly thevitreous of the eye, the entirety of both U.S. Patents are hereinincorporated by reference.

However, the design of these and other intraocular implant deliveryapparatus may be less than optimal for the large-scale manufacture of asterile, pre-loaded, ready-to-use device that can be used safely andreliably to introduce an implant into the eye. In some cases, assemblyof the apparatus may require a number of separate manufacturing andhandling steps, from producing the separate housing components, toloading the implant, to final assembly of the device. Altogether, thesesteps can lengthen the time and increase the cost of production. Qualityassurance also plays a large role in the cost and ease of manufacturingan implant delivery apparatus. Because of the small size and fragilityof ocular implants, the means used for securely retaining an implant inthe device during and after assembly is a key concern. In this regard,some apparatus may require intermediate checks and additional stepsduring and just prior to final assembly to ensure there is no loss ofthe implant during manufacture, which, while effective, are generallyinefficient for the large-scale production of such devices. It would bepreferable to have a device that permitted rapid visualization of theocular implant within the device following assembly and prior topackaging and sterilization, as well as just prior to use to confirm thereadiness of the device prior to shipping and use. An implant inspectionwindow, for example, if available, would potentially not only increasethe confidence in the batch-to-batch quality of the ocular implantdelivery apparatus, but might substantially reduce the cost and boostthe speed of manufacturing.

The apparatus described here meets these and other needs and isspecifically designed for administration of a solid rod-shaped orfilamentous intraocular implant into the anterior chamber of an eye.

SUMMARY

Described herein are methods and apparatus for safely and reliablyintroducing a solid drug formulation, such as filament or rod-shapeddrug-containing implant, into the anterior chamber (or intracameralspace) of the eye.

One embodiment provides for an apparatus for injecting an intraocularimplant into the anterior chamber of a patient's eye, the apparatuscomprising a) an elongate housing having a longitudinal axis and havinga proximal end and a distal end; b) an ejector button extending throughan opening in the housing and moveable from a first position to a secondposition in a direction normal (i.e., perpendicular) to the longitudinalaxis of the housing; c) a needle having a proximal end and a distalbeveled end, the needle extending longitudinally from the distal end ofthe housing and having a lumen extending through the length of theneedle such that an intraocular implant can be received within andtranslated through the lumen of the needle, wherein the needle isrotatable in clockwise and counter-clockwise directions about its longaxis (the imaginary segment containing the center of each end andextending the length of the needle and about which the volume of theneedle is symmetrically arranged); and d) an implant holder having aproximal and distal end and a lumen capable of receiving an intraocularimplant and holding the implant prior to activation of the apparatus,the implant holder capable of movement, upon activation of theapparatus, from a first position to a second position within the housingalong the longitudinal axis of the housing, the lumen of the holderaligned with the lumen of the needle such that an implant can slidablytranslate from the lumen of the implant holder into the lumen of theneedle upon activation of the device, and the implant holder capped atits distal end with a slit, cross-slit, or perforated membrane. Theslit, cross-slit, or perforated membrane prevents the implant fromprematurely exiting or falling out the distal end of the implant holderduring assembly, packaging, sterilization, and shipping of the apparatusand prior to activation of the apparatus and thereby blockstranslational movement of the implant from the implant holder to thelumen of the needle prior to activation of the device. However, theslit, cross-slit, or perforated membrane opens upon activation of thedevice to permit passage of the implant from the implant holder to theneedle upon activation of the device. The slit(s) and/or cross-slits orperforation(s) are included in the membrane to allow for separation ofsections of the membrane surrounding and covering the lumen opening atthe distal end of the implant holder. The central section of themembrane covering the distal end of the implant holder lumen can open,or fold back and away from the distal end of the implant holder when themembrane is moved against a forward element of the apparatus (e.g., theneedle hub), as occurs upon activation of the apparatus. The implantholder is located adjacent to the proximal end of the needle and thelumen of the implant holder is aligned with the lumen of the needle soas to permit an intraocular implant in the holder to slidably translatefrom the holder into the lumen of the needle. The device can beactivated, and an implant held by the device can be ejected, by manuallypressing the ejector button.

A push rod is provided for driving an implant out of the implant holderand through the lumen of the needle and, ultimately, out the distal endof the needle. The distal end of the needle is beveled so it can easilypierce the cornea of the eye with minimal trauma. The push rod isdisposed longitudinally in the housing and is receivable within thelumen of the implant holder and is capable of translational movementalong the longitudinal axis of the housing from a first position withinthe lumen of the implant holder to a second position within and throughthe needle lumen. In the pre-activation state of the apparatus, thedistal end of the push rod is located in the lumen of the implantholder.

A spring-driven assembly, consisting of or comprising a spring and arelease lever, is included, and is located inside the housing in theproximal half of the apparatus, to force the push rod forward along thelongitudinal axis of the housing toward the distal end of the apparatus.Accordingly, the spring generates a force that is aligned with thelongitudinal axis of the housing. In some embodiments, the force withwhich the implant is driven out of the implant delivery device by thespring-driven assembly does not depend on the pressure applied to theejector button.

In some embodiments, externally located needle-rotation knob ispositioned at the proximal end of the housing. The knob is operablyconnected to the needle at the distal end of the apparatus by a metalconnecting rod. The knob can be twisted in a clockwise orcounter-clockwise direction, relative to the longitudinal axis of thehousing, to rotate the needle in a corresponding clockwise andcounterclockwise direction, as desired.

The housing can comprise a cover top, a cover bottom, and a nose cone.The nose cone is located at the distal end of the housing. A needlebevel orientation assembly (also referred to as the needle rotationassembly) is located at the proximal end of the housing. The needlebevel orientation assembly includes the needle-rotation knob and is formanually rotating the needle, and therefore the needle bevel, in aclockwise or counter-clockwise direction relative to the long axis ofthe device prior to use and activation of the device. The housing canfurther contain implant inspection windows, which can be located in thenose cone at the distal end of the housing, for viewing the implantwithin the manufactured and sterilized apparatus. The implant inspectionwindows can permit visual observation of the implant inside the housingprior to activation of the apparatus. Two implant inspection windows maybe present on the nose cone, with one window located on one side of thenose cone and a second window located on the opposing side of the nosecone. In some embodiments, an optical element (for example, a lens) isincluded in the safety cap or the implant inspection windows or both tomagnify the view of the implant inside the apparatus, and specifically,inside the implant holder. This may aid in the detection and visualobservation of the implant.

Additionally, according to some embodiments, the apparatus can furthercomprise an implant delivery feedback window, located on the housing andproviding for observation of a visible signal that indicates activationof the apparatus. More specifically, an implant delivery feedback windowmay be included in the cover bottom or cover top to provide visualsignals to the user that the apparatus has been activated (i.e., thatthe energy stored in the spring-driven assembly inside the housing hasbeen released, as occurs, for example, when the ejector button isdepressed). Examples of visual signals can include changes in symbol(s)or letter(s), pattern or color changes, or any combination thereof.According to one embodiment, the housing cover bottom contains twoseparate delivery feedback windows, located on opposing sides of thecover bottom.

The implant delivery apparatus can comprise a solid, drug-containingintraocular implant such as an extruded biodegradable drug-containingintraocular implant, which is one type of drug delivery system. In thepresent invention, the implant is entirely contained within (i.e.,disposed within) the implant holder prior to activation of theapparatus. The implant does not enter the lumen of the needle until thedevice is activated. Similarly, the push rod does not enter or translateinto the lumen of the needle until the device is activated. The implantcan be a rod-shaped, biodegradable implant that releases a drug for anextended period such as, for example, 30 days or more. The implant cancomprise a pharmaceutically active agent (drug) effective for treating amedical condition of the eye. In some embodiments, the intraocularimplant comprises an intraocular pressure (IOP)-lowering drug such as,for example, bimatoprost or other prostamide (Woodward et al. (2008)“Prostamides (prostaglandin-ethanolamides) and theirpharmacology”British Journal of Pharmacology 153(3):410-19). Examplesinclude, but are not limited to, the prostamides described in U.S. Pat.No. 7,799,336, which is herein incorporated by reference in itsentirety. The drug-containing intraocular implant can be sized andconfigured to be receivable in and deliverable through a 28 gauge orhigher gauge needle. One example of an intraocular implant is arod-shaped biodegradable implant produced by an extrusion process with adiameter and length suitable for delivery through the needle andsuitable for placement in the anterior chamber of the eye. Thus, in oneembodiment the implant delivery apparatus comprises an intracameralimplant. The intraocular or intracameral implant can comprise abiodegradable polymer matrix and a pharmaceutically active agentassociated with the biodegradable polymer matrix. The pharmaceuticallyactive agent can be effective for treating a medical condition of theeye, and the implant can be 150 μm to 300 μm in diameter or width, 0.50mm to 2.5 mm in length, and 20 μg to 120 μg in total weight.

The intraocular implant delivery apparatus with the drug-containingimplant may be manufactured in a ready-to-use, sterile form.

The implant delivery apparatus in accordance with this disclosurecomprises a beveled needle, extending longitudinally from the distal endof the apparatus. The beveled end of the needle forms a sharp point thatcan easily penetrate the eye. The needle gauge may range from 22 gaugeto 30 gauge. In some embodiments, the beveled needle (i.e., a needlewith beveled tip) needle is a 25 gauge, 27 gauge, 28 gauge, or 29 gaugeneedle. Additionally, the needle can be a thin wall (TW) or ultra-thinwall (UTW) needle. Smaller needles (e.g., 28 gauge or higher gaugeneedles) can be used for injection of an implant into the anteriorchamber of the eye. According to some embodiments, the length of thebevel, from the tip of the needle to the heel of the bevel, is 2 mm inlength. However, various bevel lengths are possible with the presentlydescribed apparatus. The intraocular implant delivered with the presentdevice should be sized and configured such that it can slidablytranslate through the lumen (or bore) of the needle. Similarly, thelumen of the implant holder is sized to receive and hold the intraocularimplant. Examples include rod-shaped implants having a diameter or widththat permits the implant to be received in and delivered through thelumen (or bore) of the needle.

The use of needles with smaller outer diameters and the ability toorient the bevel of the needle with a rotation knob rather than havingto alter the grip on the apparatus provides added control forself-sealing methods of implant delivery into the anterior chamber of aneye.

Accordingly, one embodiment is a method for introducing an intraocularimplant into the anterior chamber of an eye using the presentlydisclosed apparatus. The method can comprise providing an intraocularimplant delivery apparatus according to the present disclosure having aneedle with a proximal end and a distal beveled end and comprising anintracameral implant, penetrating the cornea of the eye with the distalend of the needle and inserting the needle into the anterior chamber ofthe eye, ejecting the implant from the apparatus into the anteriorchamber of the eye, and then removing the needle from the patient's eye.Preferably, the puncture created by the insertion of the needle into theeye is self-sealing upon the removal of the needle. Particularorientations of the needle (e.g., bevel away from the surface of thecornea) during insertion can aid in self-sealing. For example, thepenetrating step can comprise inserting the needle into the cornea withthe bevel of the needle oriented 180° away from the surface of the eyeor cornea. According to one embodiment, the method and apparatus as setforth herein are used to introduce an intraocular implant (or moreparticularly, an intracameral implant) into the anterior chamber of apatient's eye. The patient can be a human patient in need of treatmentfor a medical condition of the eye.

The needle tip can further be configured to have particular beveleddesigns which further aid in the self-sealing method. In some forms ofthe method, the patient can have glaucoma or ocular hypertension. One ormore markings are optionally present on the exterior of the needle as anaid to measure needle advancement into the eye. In one form of themethod, the needle is inserted into the anterior chamber of the eye byinserting the needle through the cornea at a point just anterior to thelimbus (or corneo-scleral junction, where the cornea joins the scleraand the bulbar conjunctiva attaches to the eyeball). According to someembodiments, the needle is inserted into the anterior chamber to a depthof about 4 mm to about 7.5 mm, as measured from the tip of the needle tothe corneal surface where the needle first penetrates the eye. Theneedle may be pointed toward the inferior anterior chamber angle beforeejecting the implant. In one embodiment, the needle is advanced into theeye to a length of about 4 mm, as measured from the tip of the needle tothe outer surface of the eye where the needle first penetrates the eye,and the tip of the needle is pointed toward the inferior anteriorchamber angle. The ejector button is then depressed to deploy theimplant. The method may be effective for treating a medical condition ofthe eye. For example, the method may be effective for treating glaucoma,ocular hypertension (or elevated intraocular pressure), dry eye, orage-related macular degeneration.

An apparatus according to the present disclosure can include an implantholder for holding and retaining an implant during assembly and prior toactivation of the ocular implant apparatus. Unlike some other devices,the implant is not stored in the lumen of the needle but is instead heldin the lumen of an implant holder, a separately manufactured elementlocated adjacent to the proximal end of the needle inside the housing.During assembly, the distal end of the push rod is inserted into thelumen of the implant holder and implant loss is prevented during thatstep by the presence of a foil membrane affixed to the opposite end ofthe holder. The membrane is opened during activation of the device (asexplained in more detail below), but does not open during assembly orstorage of the device. The implant holder simplifies the final assemblyof the device and renders measures such as notching, crimping orplugging of the needle unnecessary, making possible the use of thinner,higher gauge needles such as 28 gauge, 29 gauge, or 30 gauge or highergauge needles. According to some embodiments, in the present apparatusthe needle is not notched, crimped, or clamped, and an O-ring or thelike is not placed on the needle during or after assembly of theapparatus. Moreover in some embodiments, the needle is not plugged orcapped with any material to prevent loss of the implant during assemblyor storage of the device.

The present apparatus may include implant inspection windows on the nosecone and the needle hub (described in more detail below) so that themanufacturer and physician can verify the presence of an intraocularimplant inside the device following assembly and prior to use of thedevice simply by looking through the window. This, too, can speed themanufacturing process and lower the cost of goods, since it may not onlypermit quick and easy visual inspection during assembly but may alsopermit an automated form of implant inspection during the qualityassurance stage of manufacture. The implant inspection window alsoprovides for a valuable final check by the end-user, the physician forexample, to confirm the readiness of the apparatus.

Additional embodiments provide for safety features which include, amongother things, a safety cap that protects the needle and those handlingthe apparatus during packaging, shipping, and use, and that also blocksthe premature, unintended depression of the ejector button at any ofthese stages. The present apparatus may also include a delivery feedbackwindow on the side of the housing, through which one or more visiblesignals are communicated to the user that the apparatus has beenactivated and that an implant has been successfully ejected.

The present apparatus may also employ a system which uses pre-set,fixed-force with which the implant is ejected. In the present apparatus,the force of implant ejection (and thus the distance the implant isejected away from the tip of the needle in liquid medium such as theanterior chamber of the eye upon activation of the apparatus) is notproportional to and does not depend on the force applied to the ejectorbutton by the user. The spring-driven assembly inside the apparatusgenerates a force against the push rod that depends on the springconstant and the degree of compression on the spring. Depression of theejector button unlocks the spring but does not contribute to the forceof implant ejection. This design may reduce variability in the implantadministration procedure and provides for a more controlled and morereproducible means of delivering implants into the eye. Thespring-driven design in the present apparatus is particularlywell-suited for injection of an implant into the anterior chamber of theeye (i.e., intracameral administration of an implant) since it helpsensure clean separation of the implant from the apparatus into thefluid-filled environment of the anterior chamber of the eye and aconsistent ejection distance within the limited space of the anteriorchamber of the eye

The intraocular delivery apparatus and its advantages according to thisdisclosure can be further understood by reference to the followingfigures and detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features will now be described with reference to thedrawings summarized below. These drawings and the associated descriptionare provided to illustrate one or more embodiments and not to limit thescope of the invention.

FIG. 1A shows a perspective view of an example embodiment of theassembled apparatus. The Distal and Proximal ends of the apparatus areindicated in the drawing.

FIG. 1B shows a perspective exploded view of the assembled apparatuswith the safety cap removed.

FIG. 1C shows a front view of the safety cap (left) and a front view ofthe implant delivery apparatus (right) with the safety cap removed.

FIG. 1D shows an end view of the safety cap (left) and an end view ofthe implant delivery apparatus (right) with the safety cap removed.

FIG. 2 shows a perspective exploded view of the implant deliveryapparatus.

FIG. 3 shows a perspective exploded view of the apparatus with the nosecone removed.

FIG. 4 depicts the apparatus in perspective and shows how the user mayrotate the needle by twisting knob 52 at the proximal end of theapparatus.

FIG. 5A shows a top view of the apparatus with the safety cap removed.

FIG. 5B shows a side view of the apparatus with the safety cap removed.

FIG. 5C shows a bottom view of the apparatus with the safety capremoved.

FIG. 6 shows a side exploded view of the apparatus, showing a side viewof each of the individual parts of the apparatus.

FIG. 7A shows a side cross-sectional view of the nose cone, needle hubassembly (including the needle hub and beveled needle), and implantholder before depression of the ejector button. Also shown is the pushrod and implant in the implant holder and the membrane affixed to thedistal end of the implant holder.

FIG. 7B shows the side cross-sectional view of FIG. 7A after depressionof the ejector button. The view shows how the implant holder membranemay fold back into the empty space in the implant holder when theimplant holder is forced against the nipple inside the needle hub. Thearrow shown at the right of the figure indicates the direction ofmovement of the push rod during implant ejection.

FIGS. 8A and 8B show examples of how the apparatus may be held andactivated by the user during use of the apparatus to deliver an implantinto the eye of a patient.

FIG. 9A shows a perspective view of the internal assemblies of theapparatus, including the needle rotation assembly 78, the push rod guideand conveyor, as well as the needle hub and beveled needle extendingfrom the distal end of the needle hub. The dotted outline indicates thelocation of the housing relative to the components. The wide,double-headed arrows show how the various components and assembliesinside the housing rotate in response to the rotation of theneedle-rotation knob 52 at the proximal end of the apparatus.

FIG. 9B shows an enlarged perspective view of the beveled needle. Thedotted, double-headed arrow indicates how the needle is rotatable inboth clockwise and counter-clockwise directions in the assembledapparatus.

FIG. 10A shows a top view of the underside or interior of the housingcover bottom 48.

FIG. 10B shows a side cross-sectional view of the distal end of thehousing cover bottom, showing the location of the rubber post 154 at thedistal end of the track 140 in the cover bottom.

FIG. 10C shows a perspective view of the inside (interior) of thehousing cover bottom.

FIG. 11A shows the underside or interior of the housing cover top 46.

FIG. 11B shows a perspective cross-sectional view of the housing covertop with the ejector button installed.

FIG. 11C shows a perspective view of the interior of the housing covertop.

FIG. 12A shows a perspective view of the needle hub assembly, includingthe beveled needle and the needle hub. The needle is overmolded with theneedle hub and is therefore permanently secured to and rotatable inunison with the needle hub.

FIG. 12B shows a top view of the needle hub assembly.

FIG. 12C shows a side view of the needle hub assembly.

FIG. 12D shows an end view of the needle hub assembly, showing theinterior of the needle hub, the nipple 62 located inside the needle hub,and the inner passageway 59 inside the nipple leading to the lumen ofthe needle. The ribs 100 inside the needle hub that grab or engage withimplant holder can also be seen in this end-on view.

FIG. 12E shows a perspective view of the needle hub assembly and theinterior of the needle hub in perspective.

FIG. 13 shows an exploded perspective view of the safety cap, nose cone,needle and needle hub (needle hub assembly), membrane, and implantholder.

FIGS. 14A and B show perspective views of the release lever.

FIG. 15A shows a perspective view of the safety cap.

FIG. 15B shows a perspective view of the safety cap with the interior ofthe cap shown.

FIG. 15C shows a side view of the safety cap.

FIG. 15D shows an end view of the safety cap, showing the interior ofthe cap.

FIG. 16A shows a perspective view of the nose cone.

FIG. 16B shows a top view of the nose cone.

FIG. 16C shows a side view of the nose cone.

FIG. 16D shows a bottom view of the nose cone.

FIG. 16E shows an end view of the nose cone, showing the interior of thenose cone.

FIG. 17A shows a side view of the apparatus prior to activation of theapparatus (i.e., prior to depression of the ejector button). The springis shown compressed against the distal end of the knob shaft. Thehousing of the apparatus is shown in cross-section.

FIG. 17B shows a top view of the distal end of the apparatus, with thesafety cap removed, and prior to ejection of the implant (i.e., prior toactivation of the apparatus). Shown is the needle extending from thenose 80 of the needle hub 58 and the nose cone in connection with thecover top. The intraocular implant 68 can be seen through the implantinspection window 112 in the nose cone. The boss section 94 of theejector button extending up through the cover top can also be seen.

FIG. 17C shows a cross-sectional side view of the apparatus, with thesafety cap removed, and prior to activation of the apparatus. The spring134 is shown compressed against the knob shaft.

FIG. 18A shows a perspective view of the ejector button.

FIG. 18B shows perspective view of the ejector button.

FIG. 18C shows a front (distal) end view of the ejector button.

FIG. 18D shows a top view of the ejector button.

FIG. 18E shows a side view of the ejector button.

FIG. 19A shows a perspective view of the implant holder with membrane106.

FIGS. 19B and C show side views of the implant holder with membrane 106.

FIG. 19D shows a back (proximal) end view of the implant holder.

FIG. 20A shows a side view of the apparatus in section prior todepression of the ejector button and, thus, prior to activation of theapparatus. Compare with post-activation view shown in FIG. 21A.

FIG. 20B shows a side view of the distal half of the apparatus insection prior to activation of the apparatus. The black single-headedarrow over the ejector button indicates the direction the button moves(i.e., downward, or in a direction normal to the longitudinal axis ofthe housing) when depressed by the user. Compare with post-activationcross-sectional view shown in FIG. 21B.

FIG. 21A shows a side view of the apparatus in section after depressionof the ejector button and, thus, after activation of the apparatus.

FIG. 21B shows an enlarged side view of the distal half of the apparatusin section after activation of the apparatus.

FIG. 22 shows an enlarged perspective view of the push rod conveyor 116,the push rod 108, the push rod guide 118, and the push rod assemblysleeve 120, which together form the push rod assembly. As shown in thefigure, the push rod conveyor is overmolded with or fixed to theproximal end of the push rod and is configured for receipt in channel126 in the push rod guide 118.

FIG. 23 shows an additional perspective view of the push rod assemblycomponents (see brief description of FIG. 22 ). This view shows theproximal end of the push rod guide, having a square orrectangular-shaped opening which can receive the distal end of the metalconnecting rod such that when the metal connecting rod is connected tothe push rod guide and is rotated clockwise or counterclockwise it will,in turn, rotate the push rod guide in identical fashion. The narrowed orrestricted opening 170 at the proximal end of the push rod assemblysleeve 120 can also be seen in this perspective view.

FIG. 24 shows a perspective view of the internal assembly of theapparatus prior to activation. The housing is shown in dotted outline.The various components of the apparatus are shown in perspective inrelation to one another in the fully assembled apparatus. Prior toactivation, the spring is compressed between the proximal end of therelease lever and the distal end of the knob shaft, as shown.

FIG. 25A shows a perspective view of the individual components of theapparatus and the connections therebetween.

FIG. 25B depicts a helical or coiled progressive spring.

FIG. 26A shows a top view of the release lever.

FIG. 26B shows a side view of the release lever.

FIG. 26C shows a bottom view of the release lever.

FIG. 27A shows a top view of the push rod guide.

FIG. 27B shows a side view of the push rod guide.

FIG. 27C shows an enlarged bottom view of the push rod guide.

FIG. 27D shows the distal end of the push rod guide.

FIG. 27E shows the proximal end of the push rod guide, which isconfigured to receive the distal end of the metal connecting rod 148.

FIGS. 28A and B show enlarged side views of the distal end of theapparatus in section following activation of the apparatus. The implant68 is shown being ejected from the tip of the needle. The distal end ofthe push rod 108 can be seen exiting the tip of the needle.

FIG. 29 shows a cross section of the mammalian eye.

DETAILED DESCRIPTION Definitions

The term “plurality” means two or more.

The term “patient” means a human or non-human mammal in need oftreatment for a medical condition of the eye.

As used herein, an “ocular region” or “ocular site” refers generally toany area of the eyeball, including the anterior and posterior segment ofthe eye, and which generally includes, but is not limited to, anyfunctional (e.g., for vision) or structural tissues found in theeyeball, or tissues or cellular layers that partly or completely linethe interior or exterior of the eyeball. Specific examples of ocularregions in the eye include the anterior chamber, the posterior chamber,the vitreous cavity, the vitreous body, the choroid, the suprachoroidalspace, the conjunctiva, the subconjunctival space, the sub-tenon space,the episcleral space, the intracorneal space, the epicorneal space, thesclera, the pars plana, surgically-induced avascular regions, themacula, and the retina.

An “intraocular implant” refers to a solid or semi-solid drug deliverysystem or element that is sized and configured to be placed in an ocularregion of the eye, including, for example, the anterior chamber. Otherocular regions of the eye into which an intraocular implant can beplaced include the vitreous body, subconjunctival space, and subtenonspace. Intraocular implants may be placed in an eye withoutsignificantly disrupting vision of the eye. Examples of an intraocularimplant include extruded biodegradable filaments, such as a rod-shapedimplant produced by a hot-melt extrusion process, comprising abiodegradable polymer matrix and a pharmaceutically active agent,associated with the polymer matrix, and cut to a length suitable forplacement in an eye. Intraocular implants are biocompatible with thephysiological conditions of an eye and do not cause adverse reactions inthe eye. In certain forms of the present invention, an intraocularimplant may be configured for placement in the anterior chamber,posterior chamber, subconjunctival space, or vitreous body of the eye.Intraocular implants can be biodegradable and may be configured in theform of a cylindrical or non-cylindrical rod produced by an extrusionprocess. According to some embodiments, the intraocular implant maycomprise an active agent effective for treating a medical condition ofthe eye.

An “intracameral” implant is an intraocular implant that is sized andconfigured for placement in the anterior chamber of the eye. Theanterior chamber refers to the space inside the eye between the iris andthe innermost corneal surface (endothelium). An intracameral implant isalso an intraocular implant that can fit into the anterior chamber angle(iridocorneal angle) of the eye without contacting the cornealendothelium and thereby without causing corneal trauma, inflammation, oredema, or iris chaffing. One example of an intracameral implant is ahot-melt extruded, biodegradable, rod-shaped filament comprising orconsisting of a biodegradable polymer matrix and an active agentassociated with the polymer matrix and cut to a length suitable forplacement in the anterior chamber of a mammalian eye (for example, ahuman eye). A rod-shaped intracameral implant can be 0.5 mm to 3 mm inlength and 0.05 mm to 0.5 mm in diameter or maximum width in the case ofnon-cylindrical rods. An intracameral implant is usually between 20 μgand 150 μg in total weight and can fit into the anterior chamber angle(iridocorneal angle) of the eye without contacting the cornealendothelium and thereby without causing corneal trauma, inflammation, oredema, or iris chaffing. For example, the intracameral implant deliveredwith the present apparatus into the anterior chamber of a mammalian eye,such as a human eye, can be 0.5 mm to 2.5 mm in length, 0.15 mm to 0.3mm in diameter, and 20 μg to 120 μg in total weight.

The intracameral implant is preferably deliverable through a 27 gauge,28 gauge, 29 gauge, or 30 gauge needle. The inner diameter of the needlemay vary, depending on whether the needle is a standard or ultra (orextra) thin-wall needle. The diameter, width, or cross-sectional area ofthe implant should be receivable in the lumen of the needle so that theimplant can slidably translate through the lumen of the needle.

An “intravitreal” implant is an intraocular implant that is sized andconfigured for placement in the vitreous body of the eye. The vitreousbody of the eye may accommodate implants larger than those used for theanterior chamber.

The terms “device” and “apparatus” are synonymous and usedinterchangeably herein to refer to the present intraocular implantdelivery apparatus (device), depicted in the attached drawings.

The term “about” means that the number, range, value, or parameter soqualified encompasses ten percent more and ten percent less of thenumber, range, value, or parameter.

The term “biocompatible” means compatible with living tissue or a livingsystem. Biocompatible implants and polymers produce few or no toxiceffects, are not injurious, or physiologically reactive and do not causean immunological reaction.

The terms “ocular condition” and “medical condition of the eye” aresynonymous and used interchangeably herein and refer to a disease,ailment, or condition which affects or involves the eye or one of theparts or regions of the eye, including the anterior or posterior regionsof the eye. The eye is the sense organ for sight. Broadly speaking theeye includes the eyeball and the tissues and fluids which constitute theeyeball, the periocular muscles (such as the oblique and rectus muscles)and the portion of the optic nerve which is within or adjacent to theeyeball. Non-limiting examples of a medical condition of the eye (i.e.,ocular condition) within the scope of the present disclosure includeocular hypertension (or elevated intraocular pressure), glaucoma, dryeye, and age-related macular degeneration. Glaucoma in a patient may befurther classified as open-angle glaucoma or angle-closure glaucoma. Inone possible method, the patient receiving an intracameraldrug-containing implant using an apparatus according to this disclosuremay have or be specifically diagnosed with primary open-angle glaucoma.A given patient having open-angle glaucoma may have low, normal, orelevated intraocular pressure. Other forms of glaucoma within thepresent disclosure include pseudoexfoliative glaucoma, developmentalglaucoma, and pigmentary glaucoma.

“Associated with a biodegradable polymer matrix” means mixed with,dissolved and/or dispersed within, encapsulated by, surrounded and/orcovered by, or coupled to.

The term “biodegradable,” as in “biodegradable polymer” or“biodegradable implant,” refers to an element, implant, or a polymer orpolymers which degrade in vivo, and wherein degradation of the implant,polymer or polymers over time occurs concurrent with or subsequent torelease of the therapeutic agent. A biodegradable polymer may be ahomopolymer, a copolymer, or a polymer comprising more than twodifferent structural repeating units. The terms biodegradable andbioerodible are equivalent and are used interchangeably herein.

“Active agent,” “drug,” “therapeutic agent,” “therapeutically activeagent,” and “pharmaceutically active agent” are used interchangeablyherein to refer to the chemical compound, molecule, or substance thatproduces a therapeutic effect in the patient (human or non-human mammalin need of treatment) to which it is administered and that is effectivefor treating a medical condition of the eye.

The term “patient” can refer to a human or non-human mammal in need oftreatment of a medical condition of the eye.

The term “treat”, “treating”, or “treatment” as used herein, refers toreduction, resolution, or prevention of an ocular condition, ocularinjury or damage, or to promote healing of injured or damaged oculartissue. A treatment is usually effective to reduce at least one sign orsymptom of the ocular condition or risk factor associated with an ocularcondition.

For purposes of describing the present apparatus, the term “proximal”refers to the end of the apparatus or apparatus component that isclosest to the needle-rotation knob 52 and that is farthest from thepatient when the apparatus is in use with the needle in contact with thepatient's eye.

The term “distal” refers to the end of the device or device componentthat is closest to the patient when the device is in use, with theneedle in contact with the patient's eye. For example, the beveled tip(or sharp end) of the needle is located at the distal end of the needleand at the distal end of the implant delivery device. The farthestdistal end of the device may be referred to as the distal sharp end ofthe device, since the needle extends or projects from the distal end ofthe device. The needle-rotation knob 52 is at the proximal end of theimplant delivery device. In this context, the orientation andconnections between components within the device may be described hereinby reference to the distal and proximal ends of the various components.The distal end being the end of the component that is located closest tothe distal end of the housing or device and the proximal end being theend located closest to the proximal end of the housing or device in theassembled device.

As used herein, “self-sealing” methods of delivering intraocularimplants into the eye refers to methods of introducing implants througha needle and into desired locations of a patient's eye without the needfor a suture, or other like closure means, at the needle puncture site.Such “self-sealing” methods do not require that the puncture site (wherethe needle penetrates the eye) completely seal immediately uponwithdrawal of the needle, but rather that any initial leakage is minimumand dissipates in short order such that a surgeon or another equallyskilled in the art, in his or her good clinical judgment, would not becompelled to suture or otherwise provide other like closure means to thepuncture site.

An embodiment of an intracameral implant delivery apparatus according tothis disclosure is depicted in FIGS. 1A-D. As shown in FIGS. 1A-1D, theintraocular implant delivery apparatus 40 is ergonomically configuredfor easy gripping and manipulation and has the general overall shape ofa pen or other writing instrument. From FIGS. 1A-1D it can be seen thatthe apparatus includes an external housing 42 and a safety cap 44, whichattaches to the distal end of the housing. Referring to FIG. 2 , it canbe seen that housing 42 is formed of a cover top 46, a cover bottom 48,and a nose cone 50. These sections may be manufactured as separatepieces and then secured or snapped together. The sections are preferablyconfigured to snap-fit together, although other known methods ofattachment are contemplated, including, e.g., gluing, welding, fusing,etc. Cover top 46 snaps onto cover bottom 48 and nose cone 50 isconfigured for receipt over and attachment to (e.g., snaps onto) covertop 46 and cover bottom 48, as is apparent from FIGS. 2 and 3 . Aneedle-rotation knob 52, which allows the user to rotate the needle 56as shown in FIG. 4 , extends from the proximal end of the housing.

As seen in FIGS. 1A-5C, nose cone 50 forms the distal end of the housing42. As seen in FIGS. 2, 3, and 6 , nose cone 50 receives needle hubassembly 54, which can include i) a needle 56 having a beveled tip 57,also referred to herein as beveled needle 56 or rotatable needle 56, andii) a needle hub 58. As can be seen in FIGS. 1A-1D, 2, 3, 6, and 7A-7B,needle 56 is attached to and extends from needle hub 58, which isreceivable in nose cone 50. In one embodiment, needle 56 is overmoldedwith or bonded to needle hub 58. Needle hub 58 is configured for receiptwithin nose cone 50, with beveled needle 56 extending through an opening60 in nose cone 50 (FIG. 3 ). As shown in the enlarged, cross-sectionviews of FIGS. 7A-7B, the lumen of beveled needle 56 is in communicationwith a cone-shaped inner passageway 59 in nipple 62 present withinneedle hub 58, such that a rod-shaped intracameral implant 68 mayslidably translate into nipple 62 and through passage 59 into the lumenof needle 56. Needle hub 58 is rotatable in clockwise andcounterclockwise directions (relative to the longitudinal axis of thehousing) inside nose cone 50. Accordingly, beveled needle 56, extendingthrough nose cone opening 60, is rotatable in the same directions sinceneedle 56 is bonded to or otherwise fixedly secured to needle hub 58.

As can be seen in FIGS. 1A-6 , an ejector button 64 extends through anopening 66 in the housing. More specifically, ejector button 64 extendsthrough an opening 66 in cover top 46.

The apparatus 40 can contain an intracameral implant 68 and may be usedto introduce the implant into the anterior chamber of a patient's eye.Depression of ejector button 64 activates the apparatus, thereby causingejection of the implant from the apparatus. The implant exits throughthe needle of the apparatus.

As shown in FIGS. 1A-5C, the presently described implant deliveryapparatus 40, though tubular in shape, comprises two flat rubber-coatedsurfaces 70 on opposite sides of the exterior of cover bottom 48 toprovide non-slip surfaces by which to firmly grip and hold the device.As shown in FIGS. 8A-8B, the flat rubberized surfaces 70 located on thehousing (and specifically on cover bottom 48) facilitate alternativegrips on the apparatus and permit the user to use either a thumb or afinger, as desired, to press ejector button 64. The provision of arotatable needle 56 further facilitates alternative grips on the devicesince the user can orient the bevel of the needle toward or away fromthe surface of the eye by twisting needle-rotation knob 52, as shown inFIG. 4 , irrespective of the user's grip on the device (FIGS. 8A-8B).

As can be understood from FIG. 4 and as shown in FIGS. 9A-9B,needle-rotation knob 52 at the proximal end of the housing is operablyconnected to needle 56 and can be used to rotate the needle in aclockwise or counter-clockwise direction (relative to the longitudinalaxis of the housing), thereby allowing one to orient the bevel of needle56, as desired, in relation to the surface of the eye. For example, thebevel can be oriented such that it faces away from the surface of thecornea as the needle is brought into contact with the eye and isinserted into the anterior chamber. Full 0° to 360° rotation of theneedle bevel is possible as well as any incremental degree of rotationtherebetween. Accordingly, needle bevel 57 may be oriented in anydirection relative to the surface of the eye regardless of whether theapparatus is gripped with the left or right hand and regardless ofwhether the user is approaching the patient from the nasal, temporal, orsuperotemporal position, and irrespective of whether the user isactivating the device with their index finger or thumb. Needle-rotationknob 52 may be snugly fitted against the housing to maintain the bevelin a given orientation once selected, and/or a frictional stop 72, inthe form of a bendable or flexible tab that presses in on a portion ofknob shaft 74 (which connects to the knob) inside the housing, isincluded in either the cover top 46 or cover bottom 48 or both to serveas resistance to the unintentional rotation of knob 52 (FIGS. 5A-5C and10A-10C). Frictional stop 72 and its action on the knob shaft 74 aredescribed in greater detail below.

As shown in the several views of the apparatus, including FIGS. 1A-6 and9A-9B, needle-rotation knob 52 contains a shaded marking or codingelement 76 on its surface to prominently indicate the orientation of theneedle bevel. As shown in FIG. 6 , coding element 76 is configured tosnap onto the end of knob 52 and is a single piece including i) aslender rectangular, finger-like, projection 75 that extends lengthwise(and in a direction along the longitudinal axis of the housing) alongthe outer surface of knob 52, and ii) a slanted back surface 77 designedto represent the bevel of the needle 56, located at the opposite(distal) end of the apparatus. As noted above, projection 75 and slantedback surface 77 of coding element 76 can be shaded (e.g., in gray orblack) so as to stand out from the base color of knob 52. As is apparentfrom FIGS. 9A-9B, the finger-like projection 75 may be elevated orraised above the surface of the needle-rotation knob.

In the fully assembled apparatus, finger-like projection 75 and slantedback surface 77 of coding element 76 are aligned with the bevel of theneedle to provide the user with a clear visual indication of theorientation of needle bevel 57 relative to any reference point on theapparatus (see FIGS. 1A-1D, 3, 4, 5A-5C, and 9 , for example). The usersimply notes the location of the shaded marking 75 on the surface of theknob or the orientation of the slanted surface 77 at the end of knob 52.In this way, even with the extremely thin, high gauge needles for whichthe bevel may be difficult to see with the unaided eye, the user canquickly rotate the beveled portion of the needle to the degree desiredand will immediately know, by looking at the coding element, in whichdirection the bevel is facing relative to the patient's eye.Needle-rotation knob 52 with coding element 76 is part of a needlerotation assembly 78, described in more detail below.

Overall the ability to freely orient the bevel of the needle relative tothe surface of the eye, as shown in FIG. 4 , can be a significantadvantage. It is envisioned that the present device can be used in anoutpatient setting wherein the patient is in the sitting or supineposition in conjunction with a slit lamp or other illumination tool. Asshown in FIGS. 8A-8B, the flat, rubber-coated surfaces 70 located on theexterior of housing 42, e.g., on cover bottom 48, facilitate alternativegrips by the user. The physician can grip the device with the left orright hand in a manner that will allow the user to use either theirthumb or index finger to press the ejector button 64. At the same timeand without changing their grip, the user can use their other hand toindependently orient the bevel away from or toward the eye, by rotatingknob 52. Alternatively, the physician can, if necessary, first orientthe needle bevel using the needle-rotation knob, and then grip thedevice in the preferred manner to inject the implant into the patient'seye. Orienting the bevel away from the surface of the eye may minimizetrauma to the eye and promote the formation of a self-sealing wound, andmay also permit the user to have a clear view of the implant as it exitsand separates from the needle and enters the anterior chamber of theeye.

The intraocular implant delivery apparatus according to this disclosurecan comprise, for example, a 22 gauge, 23 gauge, 24 gauge, 25 gauge, 26gauge, 27 gauge, 28 gauge, 29 gauge, or 30 gauge needle. The needle canfurther be a thin-wall or ultra thin-wall needle. Finer, higher gaugeneedles, such as 28 gauge, 29 gauge, or 30 gauge needles, may bepreferable for injections into the anterior chamber of the eye to createa small, self-sealing wound and to avoid fluid leakage from the eye. Thedistal end of the needle (i.e., the end that extends longitudinally fromthe distal end of the apparatus housing) is preferably beveled to createa sharp pointed tip that may easily penetrate the tissue of the eye. Theintraocular implant delivered by the device should be receivable in anddeliverable through the lumen of the needle. In one embodiment, theapparatus comprises a 28 gauge needle. In a more specific embodiment theapparatus comprises a 28 gauge needle with a wall that is 0.0015 inchesto 0.0035 inches thick (i.e., about 0.038 mm-0.089 mm thick). In oneembodiment the implant delivery apparatus comprises a 28 gauge needlewith a wall that is 0.0015 inches to 0.00225 inches thick (i.e., about0.038 mm-0.057 mm thick). In one embodiment the 28 gauge needle has awall that is 0.0020 inches to 0.0030 inches thick (i.e., about 0.051mm-0.076 mm thick). In one embodiment the 28 gauge needle has a wallthat is 0.0020 inches to 0.00225 inches thick (i.e., about 0.051mm-0.057 mm thick). In one embodiment the apparatus comprises a 28 gaugeneedle with a wall thickness of about 0.0020 inches. In otherembodiments, the apparatus comprises a 27 gauge needle with a wall thatis 0.0015 inches to 0.0040 inches thick (i.e., about 0.038 mm-0.102 mmthick), or more specifically, that is about 0.0025 inches thick. Anotherembodiment provides for an apparatus according this disclosurecomprising a 29 gauge needle, wherein the needle wall is 0.0015 inchesto 0.0030 inches thick (i.e., about 0.038 mm-0.076 mm thick), or morespecifically, about 0.0020 inches to about 0.0025 inches thick. A 30gauge needle may have a wall that is 0.0020 inches to 0.0025 inchesthick.

In other embodiments, the apparatus comprises a 22 gauge, 23 gauge, 24gauge, or 25 gauge needle. As may be appreciated by one of skill in theart, the diameter of the implant may be increased or decreased (e.g.during production) in correspondence with the inner diameter of theneedle that is present on the implant delivery device to produce animplant that can be received in and slidably translated through thelumen of the needle.

One example of an intraocular implant suitable to be received in anddelivered by the present apparatus is a rod-shaped, biodegradable,drug-containing implant formed by an extrusion process having a diameterand a length that is suitable for delivery through the needle andsuitable for placement in the anterior chamber of the eye. Such implantsmay be referred to as intracameral implants. According to someembodiments, the rod-shaped intracameral implant contained by theapparatus is 0.5 mm to 3 mm in length and 0.05 mm to 0.3 mm in diameter(or maximum width in the case of non-cylindrical rods). In oneembodiment, the intracameral implant is 0.5 mm to 2 mm in length and0.05 mm to 0.25 mm in diameter. For example, the intracameral implantcan be 100 μm to 200 μm (±10 μm) in diameter.

As shown in FIGS. 12A-12E, 13 as well as other figures such as FIGS.1A-1D, 2, 3, 6 , and 7A-7B, needle 56 is attached to and extends fromneedle hub 58, which is receivable in nose cone 50. In one embodiment,needle 56 is overmolded with or bonded to needle hub 58. As shown inFIGS. 12A-12E, needle hub 58 comprises a blunt ended nose 80 throughwhich needle 56 extends. As can be seen in FIGS. 1A-3 , needle hub nose80 extends through opening 60 in nose cone 50. The length of exposedneedle extending from needle hub nose 80 is fixed and governs themaximum distance the needle may be advanced into an eye. In the currentdevice, this length, from the distal end of nose 80 to needle tip 82(FIGS. 9A-9B and 12A-12E), is set to a length optimal for delivery of animplant into the anterior chamber of the eye (e.g., the human eye). Inaddition, the outer surface of the needle may optionally contain one ormore marks as guides to the practitioner by which to know the length ofthe needle advanced into the eye prior to activation of the device;however, needle hub nose 80 acts as an additional “safety stop” andthereby an additional safety feature, preventing further advancementinto the eye, helping prevent injuries that might otherwise occur if theneedle were inadvertently advanced too far into the anterior chamber.

According to one embodiment, the length of the needle, from the distalend of needle hub nose 80 to needle tip 82, is 4 mm to 8 mm. Accordingto another embodiment, the length of exposed needle from hub nose 80 toneedle tip 82 is 4 mm to 6 mm. The needle can be fixed to the needle hubin a manner to provide for devices with various needle lengths, asdesired. For example, the needle length from needle hub nose 82 toneedle tip 82 can be from 4 mm to 6 mm or from 4 mm to 5 mm. In someembodiments, the length of the needle is 5 mm or 7.5 mm. As shown inFIG. 13 , needle hub 58 is configured to receive and engage with animplant holder 84, further described below. Thus, implant holder 84 isreceived within needle hub 58.

An implant delivery feedback window 86, can be located on bottom cover48, as shown in FIGS. 1A-6 and 10A-10C. In general, two deliveryfeedback windows 86 are provided, each being located on opposing sidesof bottom cover 48 so that a window 86 be viewed by the user regardlessof whether the apparatus is held by the left or right hand andregardless of which side of the apparatus is facing the user. Thedelivery feedback window 86 lets the user know that the implant deliveryapparatus has been activated (i.e., that the spring has been releasedand the release lever, and therefore the push rod, has been drivenforward along the longitudinal axis of the housing toward the distal endof the apparatus. This provides the user with evidence not only withregard to the readiness of the device prior to insertion into an eye,but also with regard to the successful activation of the spring-drivenmechanism of the device during use in a patient's eye.

Activation of the device is indicated by a color or pattern change or bya texted or graphic signal or any combination thereof that can beobserved by the user through the delivery feedback window 86. Forexample, the color shown in the window may change from red to green, orgreen to red, and, to aid those with difficulty in distinguishingcolors, the pattern shown in the window may change from a first patternto second pattern distinct from the first, or, in addition to or insteadof a color change, the user may receive texted confirmation of implantejection by observing a change from one symbol such as “O” to anothersymbol such as “OK”, or vice versa, after ejector button 64 has beenpressed, i.e., after activation of the device. These color, pattern,graphic, and texted changes can be communicated to the user byimprinting one or more colors or adding one or more labels onto theside(s) of the release lever 136 (described in greater detail below), asshown in FIGS. 6 and 14A-14B. See also FIGS. 26A-26C. For example, aregion at the proximal end of the release lever can be colored red orany other distinguishable color (e.g., black, blue, purple, orange, andthe like), as depicted in FIGS. 6 and 14A-14B, and other accompanyingfigures (see section of release lever 136 labeled “Red”). Because therelease lever 136 must slidably translate forward, along thelongitudinal axis of the housing, toward the distal end of the apparatusunder the action of the spring when the ejector button is depressed, theforward movement of the release lever indicates activation of thedevice. Thus, activation of the apparatus can be clearly communicated tothe user by providing a window into the housing (a delivery feedbackwindow) to view the change in location of the release lever from a firstposition to a second position. For this purpose, two discrete sectionsalong the lateral edge of release lever 136 can be labeled with twodifferent colors, patterns, and/or text symbols. A first color, pattern,or text symbol will show in and be visible through the delivery feedbackwindow prior to activation, but will slide out of view as a seconddifferent color, pattern, or text symbol slides into view as the releaselever is forced forward along the longitudinal axis of the housingtoward the distal end of the apparatus by the spring followingactivation of the device. In one embodiment, the release lever as awhole is green (e.g., the release lever may be cast of a green-coloredplastic) and a single region at the proximal end of the release lever ispainted or differently colored (e.g., red) (See FIGS. 6 and 14A-14B) andmay, optionally, be further labeled with text to clearly indicate whenthis region of the release lever slides into view of the deliveryfeedback window following activation of the apparatus.

As previously stated and as shown in FIGS. 1A-1D, 5A-5C, 6, and 13 theintracameral implant delivery apparatus 40 can further comprise a safetycap 44. As shown in FIGS. 1A-1D, safety cap 44 is designed to both guardthe needle and to prevent premature or unintentional activation of thedevice during shipping and handling. Safety cap 44 snaps and/or twistsonto the distal end of the housing 42. Specifically, safety cap 44includes flexible or bendable tabs 89 a and 89 b located on opposing,upper and lower sides of cap 44 (FIGS. 1A-1D, 5A-5C, and 13 ). Each tab89 a and 89 b comprises bosses (or projections) 92 that are configuredto snap-fit into recesses 88 a-d, respectively, present on the upper andlower surfaces of nose cone 50 and on cover bottom 46 and cover bottom48 (FIGS. 1A-3 and 5A-5C). As can be seen in FIGS. 1A-1D, 6, and 13 ,safety cap 44 is designed to receive nose cone 50 and, is of sufficientlength and volume to guard and prevent damage to needle 56 extending outthrough the opening in the nose cone 50. The safety cap further guardsthe user against injury by the needle during handling.

As seen in FIGS. 1A-1D and 15A-15D, safety cap 44 comprises a finger 90that projects over ejector button 64 when the cap is snapped intoposition on nose cone 50. In this manner, finger 90 guards ejectorbutton 64, preventing unintentional depression of button 64 andactivation of the device. Additionally, as shown in FIGS. 13 and15A-15D, boss-like projections 92 are present on each flexible tab 89.These are specifically located at the far bendable end of each tab.Bosses 92 are received into recesses 88 a-d on the housing. On thebottom of the housing, these projections 92 click into recesses 88 c andd present on nose cone 50 and cover bottom 48, respectively. See alsoFIGS. 16A-16E. On the top of the housing, projections 92 of the uppertab 89 a click into recesses 88 a and 88 b present on nose cone 50 andcover top 46, respectively. When clicked into recesses 88 a and 88 b,one projection 92 comes to rest against a boss section 94 present onejector button 64. See FIGS. 18A-18E. As may be understood by referenceto FIGS. 2, 5A-5C, 11A-11C and 17A-17C, boss section 94 of ejectorbutton 64 extends up through an opening 96 in cover top 46. Activationof the device requires that ejector button 64 be pressed down in adirection perpendicular (i.e., normal) to the longitudinal axis of thehousing, which in turn requires that the front section of the button 64,containing the boss 94, move an upward direction away from the device.See FIGS. 18A-18E, showing enlarged views of button 64, boss 94, and thecylindrical posts 95 about which the button 64 pivots when present inthe assembled apparatus. As may be appreciated by reference to FIGS.19A-19D, 20A-20B, and 21A-21B, ejector button 64 pivots aboutcylindrical posts 95, projecting laterally from each side of button 64,in a see-saw fashion so that, as one end of the button is pressed down,the other end (containing boss 94) goes up. Cylindrical posts 95 clipinto U-shaped jaws 47 present on the underside of cover top 46, as shownin FIGS. 11B and C. The jaws secure the button 64 to the cover top butpermit rotational movement of the posts 95 within the jaws. Thus, button64 is able to move in see-saw fashion when clipped into the jaws 47.Projection 92 on the inner surface of flexible tab 89 a of safety cap 44blocks the upward movement of boss 94 present on the front section ofejector button 64, which together with finger 90, which projects outover the button, prevents the unintentional depression of the ejectorbutton 64 and inadvertent activation of the intraocular implant deliverydevice 40 during manufacture, packaging, shipping, and routine handling.

Safety cap 44 can be designed in a manner so that it is removed from theapparatus by either pulling it off the apparatus in one motion or in amanner that requires it first be twisted clockwise or counterclockwise(see wide arrow on cap in FIGS. 1A-1D) before it can be pulled off theapparatus.

Turning now to needle hub 58, it can be seen from the several views ofthe apparatus accompanying this description, including FIGS. 2, 3, 6,7A-7B, 12A-12E, and 13 that beveled needle 56 extends from the distalend of needle hub 58. The needle hub has an interior configured with i)a membrane-opening nipple 62 and ii) a plurality of ribs 100 or otherelements configured for catching, grabbing, or engaging recesses orindentations 102 in the proximal end of implant holder 84, such thatrotation of implant holder 84 in a clockwise or counterclockwisedirection causes rotation of needle hub 58 and needle 56, fixed toneedle hub 58, in the same clockwise or counterclockwise direction tothe same degree (FIGS. 12A-12E, 13, 19A-19D). The externally locatedknob 52 at the proximal end of the housing (see FIGS. 1A-5C) allows theuser to rotate implant holder 84 and thereby needle 56 prior to deliveryof the implant, as described in more detail below. Needle hub 58 isreceivable within the interior of nose cone 50 such that the needleextending from the distal end of the needle hub (and specifically fromthe needle hub nose 80) will thereby extend through opening 60 in nosecone 50.

Prior to ejection from the apparatus, the drug-containing intracameralimplant is held within the apparatus in implant holder 84, as depictedin FIGS. 7A-7B and 20A-20B. Enlarged views of implant holder 84 areshown in FIGS. 19A-19D. As may be understood from the description aboveand the attached figures, implant holder 84 is receivable in needle hub58 and is further configured for snap-fit attachment to push rod guide118. More specifically, the proximal end of implant holder 84 fixedlyattaches to the distal end of push rod guide 118.

As shown in FIG. 7A, prior to activation of the apparatus, theintraocular implant 68 is secured in the implant holder by means of amembrane 106 at one end (the distal end of the implant holder) and apush rod 108 at the other end (the proximal end of the implant holder).The implant holder contains a bore or lumen. The implant is loaded andheld within the lumen of the implant holder. The push rod 108 isgenerally cylindrical and can be made of a metal or metal alloy. Thediameter of the push rod should be such that the push rod is freelyreceivable within the lumen of the implant holder and within the lumenof the needle used with the apparatus. In one aspect, and as can be seenin FIG. 19A, the membrane 106 is cross-slit to allow for transfer of theimplant 68 from the implant holder 84 to the needle 56 upon activationof the device. According to some embodiments, other slits in addition tothe cross-slit may be included in the membrane. Membrane 106 may be madeof a metal-based foil such as an aluminum foil or other suitablematerial that provides a suitable barrier to the implant during storageof the device but that can be slit, partially slit, or perforated orfolded back when forced against nipple 62 inside the needle hub 58 uponactivation, as schematically depicted in FIGS. 7A and 7B. According tosome embodiments, membrane 106 is an aluminum foil membrane that is 10μm to 60 μm thick. As previously discussed, the inclusion of slits orcross-slits or both can facilitate the separation of sections of themembrane and promote clearance of the membrane away from the distal endof the implant holder to allow for translation of the implant from theholder to the lumen of the needle during activation of the device. Asshown in FIGS. 7A-7B, nipple 62 inside needle hub 58 has a cone-shapedpassageway 59 that leads into the lumen of needle 56 and, which, becauseof its cone shape, helps guide the implant into the lumen of the needle56 when the implant is driven forward by push rod 108.

The implant holder 84 is made of a transparent material, such as a clearplastic (e.g., a polycarbonate), such that the implant 68 can be seenwithin the holder. According to one embodiment, the implant holder isdesigned for use with cylindrical or non-cylindrical rod-shaped implantsthat have a diameter and are cut to a length suitable for placement inthe anterior chamber of an eye. As shown in FIGS. 1A-5C, 9A-9B, 12A-12E,and 13 , implant inspection windows 112 and 112′ (112 prime), areincorporated into nose cone 50 and needle hub 58, respectively. As maybe appreciated from FIGS. 12A-12E and 16A-16E, two inspection windows112 and two inspection windows 112′ are present on the nose cone andneedle hub, respectively. The two windows on the nose cone (and implantholder) are separated from one another by about 180°, being located onopposing sides of the nose cone (and implant holder). In the fullyassembled apparatus, the windows 112 on the nose cone can be alignedwith windows 112′ on the implant holder by twisting needle-rotation knob52, such that in the fully assembled apparatus the two windows 112 canbe aligned immediately above and below windows 112′ on the implantholder (located inside the device) so that a beam of light can passthrough all four windows and the presence of an implant in the apparatus(and implant holder 84) can be visually confirmed by looking througheither of the inspection windows 112 in nose cone 50 (FIGS. 16A-16E), asdepicted in FIGS. 17B and C. For example, an implant inspection window112 is located on the top and bottom surfaces of nose cone 50, which isconnected to (and snaps onto) both the cover top 46 and cover bottom 48.Needle hub 58 located inside nose cone 50 contains matching windows 112′aligned with windows 112 in nose cone 50 so that one may visualize theintracameral implant 68 in the implant holder within the needle hub. Theimplant inspection windows provide a useful quality control feature,enabling one to confirm the presence of the implant in the device priorto packaging, prior to sterilizing, and prior to actual use in any eye.To further facilitate visual inspection and verification of the implantin the assembled apparatus, one embodiment provides for implantinspection windows 112 in the nose cone that comprise or that are in theform of a magnifying element, lens, or other optical element thatenlarges or magnifies the view of the implant inside the implant holder.An optical element may also be included in the safety cap to magnify theimplant image and the safety cap may be made of clear plastic materialthat permits one to easily see the intraocular implant inside thehousing of the assembled apparatus.

Membrane 106 can be affixed, glued, welded (sealed onto the holder byheat), or bonded to the distal end of implant holder 84. The membrane106 affixed to the distal end of the implant holder 84 is preferably athin pliable material that can bend, fold back, or otherwise open whenforced against the membrane-opening nipple 62 inside needle hub 58. Insome embodiments, the membrane is a thin metal or metal- or metal-alloybased foil. In one embodiment the membrane is made of an aluminum foiland is cross-slit (e.g., in the shape of an “X”) so that it may foldback when it is forced against the nipple 62 inside needle hub 58 (FIGS.7A-7B, 20A-20B, and 21A-21B). In addition to the first cross-slit,second slits may be added to the membrane, such as at the periphery ofthe cross-slit, to further promote clearance of the membrane materialupon contact with the nipple 62.

Implant holder 84 is moveable in a direction along the axis of thehousing from a first position to a second position against nipple 62inside needle hub 58. Movement of the implant holder from a firstposition to a second position against nipple 62 inside the needle huboccurs upon depression of ejector button 64. When membrane 106 at thedistal end of the implant holder is forced forward against nipple 62,nipple 62 forces membrane 106 open, by, for example, causing cross-slitsections of the metal-foil membrane to fold back, allowing forunrestricted passage of the implant 68 from the lumen of implant holder84 into the lumen of needle 56 (compare FIGS. 20A-20B and 21A-21B andsee FIGS. 7A-7B). Passage of the implant from the implant holder 84 tothe needle is driven by push rod 108, as described below.

According to one embodiment, the implant holder is loaded with a single,rod-shaped, intraocular implant. However, other embodiments provide fora method of introducing two or more solid, rod-shaped implants into anocular region of the eye (e.g., the anterior chamber or vitreous), usingthe present apparatus. Delivery of two small implants, instead of onelarge implant, may be one means for delivering a larger dose of activeagent into the eye. Thus, in some embodiments the implant holder isloaded with two or more rod-shaped, drug-containing, intraocularimplants.

Accordingly, the intracameral implant delivery device can furtherinclude a push rod assembly 114 (shown in FIGS. 22 and 23 ) including i)a push rod 108, ii) a push rod conveyor 116, iii) a push rod guide 118,and iv) a sleeve 120, wherein sleeve 120 is engaged with ejector button64 such that downward movement (e.g., depression) of ejector button 64causes (i.e., is translated into) forward movement of sleeve 120 and,thereby, forward movement of push rod assembly 114 along thelongitudinal axis of the housing toward (i.e., in the direction of) thedistal end of the device, as shown schematically in FIGS. 20A-20B and21A-21B. Push rod 108 and push rod guide 118 each have proximal anddistal ends. As can be seen in FIG. 22 , sleeve 120 is configured as ahollow cylinder with an inner diameter sufficient to slide over andreceive the proximal end of push rod guide 118. As shown in FIG. 23 ,sleeve 120 has a restrictor 170 at one end (i.e., the opening at one endof the sleeve (the proximal end) is narrower than the other end) toprevent the sleeve from sliding over the entire length of push rod guide118. As shown in FIGS. 22 and 23 , the sleeve 120 further comprisesforward and rearward guide posts 122 and 122′ (122 prime), respectively,on opposing sides (two posts on each side) of its exterior for engagingwith wings 124 that are present on each side of ejector button 64. Theforward posts 122 correspond to those at the distal end of the sleeve.As shown in the several views of the apparatus, including FIGS. 2, 17A,20A-20B, 21A-21B, and 24 , the wings of the ejector button fit betweenthe forward and rearward guide posts. Wings 124 of ejector button 64curve forward such that depression of the button causes the wings 124 tosweep sleeve 120 forward toward the distal end of the apparatus. Thisoccurs because, as button 64 is depressed, it pivots about thecylindrical posts 95 that are clipped into cover top 46. At the sametime, as button 64 pivots about posts 95, the curvature of the wings 124maintains a constant frictional force against the forward posts 122 onthe sleeve 120. Thus, because the opening in sleeve 120 is sufficientlynarrow at its proximal end such that the sleeve cannot slide over theproximal end of push rod guide 118, sleeve 120 converts downward forceon ejector button 64 (i.e., the force applied to depress button 64) intoforward longitudinal movement of push rod guide 118 toward the distalend of the apparatus. Because implant holder 84 is fixedly secured tothe distal end of push rod guide 118 (as may be apparent from FIGS. 6,20A-20B, 21A-21B, and 25A-25B, and as discussed below), longitudinalmovement of push rod guide 118 toward the distal sharp end of theapparatus results in longitudinal movement of the implant holder 84toward nipple 62 within needle hub 58, ultimately causing implant holdermembrane 106 to be forced against nipple 62 inside needle hub 58 (seeFIGS. 7A-7B, 20A-20B, and 21A-21B, for example). Nipple 62 therebyforces open membrane 106, by, for example, forcing the cross-slitsections of membrane 106 to fold back. Communication between the lumenof the implant holder and the lumen of needle 56 is thereby establishedsuch that the implant can slidably translate from the lumen of theimplant holder into the lumen of the needle upon movement of the pushrod 108. As can also be understood from the several views of theapparatus in the attached figures, because the wings 124 of ejectorbutton 64 are disposed between forward and rearward guide posts,designated as 122 and 122′ (122 prime), respectively, on either side ofejector button 64, these posts further serve to prevent the sleeve frominadvertently falling out of position during assembly of the apparatus.

As shown in FIGS. 7A and 20A-20B, in the pre-activation state of thedevice 40, a portion of the distal end of push rod 108 resides inimplant holder 84 and is in contact with, is adjacent to, or abuts theintraocular or intracameral implant 68, thereby preventing backwardmovement of and inadvertent, unintentional loss of the implant from theimplant holder during assembly and prior to activation of the apparatus.Thus, prior to activation of the apparatus and prior to deployment ofthe implant in the eye, the intraocular implant 68 is secured withinimplant holder 84 by membrane 106 at one end (the distal end) of theimplant holder 84 and push rod 108 at the other end (proximal end) ofthe implant holder 84. As discussed above, the intraocular implant canbe an intracameral implant.

As shown in FIGS. 9A-9B, 22 and 23 , push rod conveyor 116 is configuredto be received within a groove or channel 126 present in push rod guide118. The push rod 108 is overmolded with or bonded to the push rodconveyor 116, which as shown in FIGS. 22 and 23 , is a semi-circular,“U” shaped element having a tongue that fits into the groove 126 in thepush rod guide 118 and having flanking members that curve around theoutside of push rod guide 118. With its U-shaped structure, push rodconveyor 116, and therefore the push rod 108 to which it is bonded orfixed, can slide forward along the longitudinal axis of the housingwithin the channel 126 present in push rod guide 118, toward the distalend of the device, from a first position to a second position along thelongitudinal axis of the housing. As shown in FIGS. 22, 23, and 27A-27Eside bumps 180 are provided on each side of push rod guide 188 to keepthe push rod conveyor and associated push rod from prematurely slidingthrough channel 126 prior to activation of the spring. The stroke lengthof channel 126 (the distance conveyor 116 can travel in channel 126) inpush rod guide 118 can vary, but may be from 10 mm to 50 mm, forexample.

As discussed above, push rod 108 is configured for slidable receiptwithin the lumen of implant holder 84 and the lumen of the needle 56extending from the needle hub 58. Push rod 108 is of sufficient lengthto displace an implant loaded in the implant holder from the holder intothe needle lumen and through the length of the needle to thereby ejectthe implant from the distal end of the needle (or needle tip). The pushrod can be a metal or metal alloy cylindrical rod 10 mm to 50 mm long,although the length of the push rod can be varied. The diameter of thepush rod can vary, but should be sized so that the push rod is slidablyreceivable within the lumen of the implant holder and the lumen of theneedle attached to the needle hub.

Implant holder 84 locks or snaps onto or is fixedly secured to thedistal end of push rod guide 118. In one form of the device, the implantholder has two or holes 128 that can receive and cling to two or moreprongs or snap hooks 130 present on the distal end of the push rod guide118 (FIGS. 19A-19D, 22, 23, 25A-25B, and 27A-27E). Enlarged views ofpush rod guide 118 are shown in FIGS. 27A-27E. In this manner, the pushrod guide and implant holder are interlocked and can be rotated inunison as a single assembly.

As may be understood from the several figures (e.g., FIGS. 2, 9A, and 24) and preceding disclosure, the intracameral implant delivery apparatuscan further comprise a spring-driven assembly for ejection of theintracameral drug-containing implant from the device and a needlerotation assembly 78 for rotating the beveled needle 56 attached toneedle hub 58 and extending from the distal end of the apparatus. Thespring-driven assembly is engageable with the push rod (and specificallywith the push rod conveyor) and forces the push rod through the lumen ofthe implant holder and the lumen of the needle following activation ofthe apparatus.

The spring-driven assembly comprises or consists of i) a spring 134, andii) a release lever 136 for ejection of the implant from the device(see, for example, FIGS. 24, 25A-25B, and 26A-26C). In the presentapparatus, the distance the implant 68 is driven away from the tip ofthe device by the spring-driven assembly depends, in part, on the springused in the device (e.g., the spring constant and the potential energystored in the spring in its compressed state) and is independent of andnot proportional to the force applied to the button by the user.According to one embodiment, the present apparatus comprises a helicalor coiled spring. The helical spring may be characterized according tothe formula F=kx, where F is the force needed to extend or compress thespring by some distance x, and where k is a constant factorcharacteristic of the spring. For example, k may be considered to be ameasure of the “stiffness” of the spring. Accordingly, the force F withwhich an implant is ejected from the current apparatus (expressed inNewtons, for example) is proportional to the spring constant k and thedisplacement x of the free end of the spring relative to its position inthe relaxed state. In one embodiment, the apparatus contains a helicalspring, as seen in FIG. 25A. In a more specific embodiment the helicalspring is a progressive helical spring as shown in FIG. 25B.

According to one method for using the present apparatus to deliver animplant into the anterior chamber of any eye, the needle is insertedinto the anterior chamber of an eye to a depth of about 5 mm, asmeasured from the tip 82 of the needle inside the eye to the surface ofthe cornea where the needle first penetrates the eye, and the implant isejected a distance of at least 2 mm to 4 mm, but not more than 5 mm or 6mm, away from the tip 82 of the needle 56, as measured from the back endof the implant to the tip of the needle, following activation of theapparatus. Preferably, the implant delivery apparatus ejects theintracameral implant into the anterior chamber of the eye with a forcethat is sufficient to drive the implant away from the tip of the needleso that it does not adhere to the needle as the needle is withdrawn fromthe eye, but insufficient to cause the implant to strike or ricochet offthe iris or tissues on the other side of the anterior chamber. Animplant that adheres to the needle tip as the needle is withdrawn fromthe eye may become lodged in the cornea as the needle is withdrawn,possibly leading to undesirable effects such as corneal edema andinflammation. On the other hand, implants that are ejected tooforcefully may strike the iris or side of the anterior chamber, whichmay cause hemorrhages. Ejection distances can be experimentally measuredin vitro by ejection into, for example, a balanced salt solution (BSS)at to 37° C. In some embodiments the apparatus ejects the intraocularimplant a distance of 2 mm to 4 mm away from the tip of the needle in aliquid medium, such as BSS at a temperature of to 37° C. The measurementmay be taken, for example, from the back end of the implant to the tipof the needle.

Release lever 136 is positioned in the apparatus for slidable movementalong the longitudinal axis of the housing axis and toward the distal,needle-tipped end of the device. As shown in FIGS. 6, 10A-10C, 14A-14B,25A-25B, and 26A-26C, release lever 136 is a hollow cylindrically shapedmember having proximal and distal ends and capable of receiving andsliding over push rod assembly sleeve 120. On opposing sides of itsexterior, the release lever contains rails 138 (or raised contouredsurfaces) extending along the longitudinal length of the release lever.Rails 138 are configured for receipt in and are slidable within tracks140 located inside the housing on the underside of cover top 46 andinterior surface of cover bottom 48. Tracks 140 are aligned with thelongitudinal axis of the housing and extend along the length of covertop 46 and cover bottom 48. Consequently, due to receipt of rails 138 intracks 140, the release lever is not rotatable within the housing but isslidable within the housing along tracks 140 in a forward directiontoward the distal end of the device. As shown in FIGS. 6, 14A-14B, 25A,and 26B, and as may be understood from FIGS. 2, 17A-17C, and 24A-24B,the release lever 136 is also configured with slots 142 through whichguide posts 122 and 122′ on push rod assembly sleeve 120 can be receivedand slidably translate. The diameter of the distal end of the releaselever, however, is too small to receive and therefore cannot slide overpush rod conveyor 116. In the pre-activation state of the apparatus,push rod conveyor 116 is positioned against the distal end of releaselever 136 and conveyor 116 is sufficiently large (e.g., has a sufficientdiameter or width) such that it cannot be received within release lever136. Accordingly, forward translation of release lever 136 along thelongitudinal axis of the housing (toward the distal end of the device)results in forward longitudinal movement of push rod conveyor 116 and,consequently, forward movement of push rod 108. Since the distal end ofrelease lever 136 is sized so that it cannot slide over push rodconveyor 116, it must instead push against conveyor 116 when the releaselever is forced forward, toward the distal end of the apparatus, byspring 134.

As can be understood from FIGS. 2, 6, 17A-17C, 24, and 25A-25B, theproximal end of release lever 136 is in contact with spring 134. In thepre-activation state of the implant delivery device, release lever 136compresses spring 134 against the distal end of knob shaft 74, and keepsthe spring in a compressed state until the ejector button is depressed.This is made possible by a flexible tab 144 present on the release lever(seen in FIGS. 2, 14A-14B, 24, 25A, and 26A). Tab 144 is configured witha T-shaped protuberance 145 (FIGS. 14A-14B) that is too wide to passthrough the gap between gate posts 147 present in track 140 on theinterior of cover top 46 (FIGS. 11A-11C). As can be seen in FIGS.11A-11C, track 140 in cover top 46 includes two gate posts 147 justproximal to the ejector button 64 inside cover top 46. In thepre-activation state of the apparatus, the two posts 147 prevent forwardmovement of the release lever (i.e., movement along the longitudinalaxis of the housing in a direction toward the distal end of the device)due to the presence of the T-shaped protuberance 145 that catches on thegate posts 147. However, depression of ejector button 64 bends tab 144down, which in turn allows protuberance 145 to pass over the gate posts.With its forward movement no longer blocked, the release lever 136 isdriven forward by the spring toward the distal end of the apparatus (seebefore- and after-activation views in FIGS. 20A-20B and 21A-21B).Forward movement means translation along the longitudinal axis of thehousing toward the distal end of the apparatus.

Thus, as can be understood from the foregoing discussion and theattached figures, manual depression of ejector button 64 results in i)forward movement of push rod assembly sleeve 120 (and thereby forwardmovement of the entire push rod assembly 114 and implant holder 84,which is attached to the push rod assembly) along the longitudinal axisof the housing, and ii) detachment of release lever 136 from housingcover top 46, which thereby releases the mechanical energy stored in thecompressed spring, thereby driving the release lever forward. As it isdriven forward by the spring 134, the release lever 136, in turn, drivesthe push rod conveyor 116 forward through channel 126 present in pushrod guide 118. Because the push rod and push rod conveyor are fixedlysecured to one another, forward movement of push rod conveyor 116 drivespush rod 108 forward through the lumen of the implant holder and thelumen of the needle, thereby causing ejection of the intracameralimplant out the distal, beveled end of needle 56.

Referring to FIGS. 9A-9B and 25A-25B, the needle rotation assembly 78comprises or consists of i) a needle-rotation knob 52 and the associatedcoding element 76, which shows the orientation of the needle bevel, ii)a knob shaft 74, and iii) a metal connecting rod 148. The metalconnecting rod 148 operably links needle-rotation knob 52 at theproximal end of the device with push rod guide 118. As schematicallyshown by the arrows in FIGS. 4 and 9A-9B, metal connecting rod 148transmits rotation of needle-rotation knob 52 by the user into rotarymotion of push rod guide 118 and, thereby, into rotary motion of needle56 at the distal end of the implant delivery apparatus. For thispurpose, the distal and proximal ends of the metal connecting rod may beshaped to fit or mate with cavities present on the distal end of knobshaft 74 (described below) and at the proximal end of push rod guide118. As is clear from FIGS. 2, 9A-9B, and 25A-25B as well the otherviews of the apparatus, knob 52 is configured to receive and operablyengage with the proximal end of shaft 74. Thus, by rotating knob 52,torque can be applied to the metal connecting rod, the push rod guide,the implant holder, and the needle hub.

As explained above, needle-rotation knob 52 is operably connected tometal connecting rod 148 by way of a knob shaft 74. As shown in FIGS.25A-25B, for example, knob shaft 74 is a cylindrically shaped elementhaving distal and proximal ends, wherein the proximal end is configuredto be received in and gripped by knob 52 inside the housing, and whereinthe distal end comprises a recess configured to mate with the proximalend of metal connecting rod 148. As can be further seen in FIGS. 2, 6,9A-9B, 24, and 25A-25B, Knob shaft 74, is configured with first, second,and third coaxial disks spaced at intervals along the axis of shaft 74:the first disk (149′) (149 prime), acts as a backstop to spring 134, thesecond disk (149″) (149 double prime) provides frictional resistance tothe rotation of the shaft (by contact with tab 72 on cover bottom 48),and the third disk (149′) (149 triple prime) provides flush contact withand receipt in knob 52. As may be apparent, Knob shaft 74 with the threecoaxial disks can be manufactured as a single moldable plastic element.Referring to FIGS. 17A-17C, 20A-20B, 21A-21B, the second disk 149″ ofknob shaft 74 can be positioned in frictional contact with tab 72 oncover bottom 48. In this way, a small frictional force produced by tab72 pressing against shaft 74 (via disk 149″) acts as resistance to therotation of knob 52. This friction force helps maintain the orientationof the needle bevel once selected by the user and helps preventunintentional rotation of the needle during handling. Tab 72 is flexibleyet resilient and may be formed of a moldable plastic piece and isformed as part of the cover bottom 48.

Due to the nature of the spring-driven mechanism, including the lengthof the push rod, and the particular assembly developed for the apparatusdescribed herein, a portion of the distal end of the push rod 108 mayexit the tip of the needle during ejection of the implant, as depictedin FIG. 21B and FIGS. 28A and B. This can happen because the push rodconveyor 116 and the push rod 108, which is associated with the push rodconveyor, are not fixedly attached to the release lever 136, the spring134, or any other component of the spring-driven assembly. The push rodconveyor 116, is propelled forward, along the longitudinal axis of thehousing and toward the distal end of the apparatus, through channel 126in push rod guide 118 and, thus, push rod 108 is propelled through thelumen of the implant holder and the lumen of the needle, as aconsequence of the release lever striking push rod conveyor 116. Formost of the length of channel 126 in guide 118, push rod conveyor 116 isactively driven forward (i.e., is driven from a proximal position to amore distal position along the length of the housing) through the pushrod guide toward the distal end of the apparatus by the release lever136, which, in turn, is driven forward by the spring 134. However, ascan be seen in the post-activation view depicted in FIGS. 21A-21B, andcomparing to the pre-activation view depicted in FIGS. 17A-17C and20A-20B, forward movement of the release lever is, eventually, abruptlyhalted by a rubber post 154 present distally in track 140 of coverbottom 48 (see also FIGS. 2 and 10A-10C). Specifically, forwardprocession of the release lever is blocked when lower rail 138 of therelease lever makes contact with rubber post 154 in track 140 of thecover bottom. Rubber post 154 is an extension of the rubber-coatedsurface 70 or grip that is part of cover bottom 48 (see FIG. 5C). Thus,rubberized surface 70, which can be affixed, glued, or bonded to coverbottom 48, extends into the interior of cover bottom 48. The rubber postcan serve to dampen the motion of the spring mechanism or spring-drivenassembly, and because it is rubber, may also have the added effect ofreducing the noise associated with activation of the device. As may alsobe appreciated, the position and variations in the position of therubber post in track 140 in the cover bottom may influence the distanceof an implant is ejected from the tip of the apparatus.

Though forward movement of release lever is suddenly stopped by rubberpost 154, the stroke length of channel 126 in push rod guide 118 is suchthat there remains about 1-2 mm of additional channel 126 through whichthe push rod conveyor 116 may continue to travel before reaching the endof its path through the channel. Thus, for the last 1-2 mm of forwardmovement, the conveyor 116 and push rod 108 are no longer being activelypushed from behind by the release lever but instead travel freely inpush rod guide 118. Upon hitting the end of the guide 118, the conveyor116 and push rod 108, which is attached to the conveyor, are propelledor bounced backward in the opposite direction toward the proximal end ofthe device. The length of the push rod may be such that the tip of thepush rod may momentarily exit out the end of the needle tip (as depictedin FIGS. 28A-28B) and then quickly retract when the push rod conveyorstrikes the end of track or channel 126 in push rod guide 118.

This ejection-retraction action of the push rod upon activation of thedevice, wherein the distal end of the push rod momentarily exits the tipof the needle before retracting back inside the lumen of the needle, canbe beneficial because it may help drive the implant away from the tip ofthe needle and into the fluid-filled medium of the anterior chamber.This may be a further advantage of the device because it may reduce andmay eliminate the chance that the implant may adhere to the needlefollowing ejection. Small air pockets that can form near and around theimplant during assembly of an ocular implant delivery device are oftenreleased with the implant during ejection. In a fluid-filled environmentsuch as the anterior chamber, these air pockets can manifest in the formof a small air bubble or air bubbles, which may adhere to both theimplant and the needle tip, possibly tethering the implant to the needleor needle after ejection. Withdrawing the needle from the eye while theimplant remains adhered to the needle can lead to complications for thepatient. With the present device, however, a portion of the push rodexits out of the needle tip and then quickly retracts back inside thedevice. This exit and retraction action of the push rod may help breakthe surface tension of any air bubbles that attach to the implant andthe tip of the needle when the implant is pushed out of the needle andmay help drive the implant away from the device into the intracameralspace (anterior chamber) of the eye.

As stated above and as shown in FIGS. 7A-7B and 20B, prior to activationof the apparatus, push rod 108 is positioned such that the intracameralimplant is retained and secured in implant holder 84 by means of themembrane 106 at the distal end of the holder 84 and the push rod 108 atthe proximal end of the holder 84. The membrane may be circular ornon-circular and is sized to fully cover or block the distal end of theimplant holder and is partially cut. For example, the membrane may beslit, cross-slit, or perforated, and made of such material that movementof the implant holder from a first position to a second position (in adirection away from the proximal end of the apparatus and toward thedistal end of the apparatus (i.e., toward the needle) forces themembrane open or folds the membrane back and away from the lumen of theimplant holder to allow for transfer of the implant from the lumen inthe implant holder to the lumen of the needle. The opening or foldingback of the membrane 106 upon activation of the apparatus (i.e., upondepression of the ejector button) is schematically depicted in FIGS.7A-7B and 28A-28B and 20A-21B. As can be seen in the FIGS. 7A-7B, thedistal end of the implant holder is fashioned such that it contains aninner smaller cylinder within a larger outer cylinder (the smallercylinder constituting the lumen and containing the intraocular implant68). As can be further understood by reference to FIGS. 7A and 7B, thereis a void between the inner and outer cylinders into which the membrane106 may be stuffed or folded as the implant holder 84 is driven forwardagainst nipple 62.

As previously discussed, engaged with the proximal end of push rod 108via push rod conveyor 116 is a compressed spring-driven assembly(including the release lever 136 and the spring 134), which, whentriggered, is capable of forcing push rod 108 forward through theimplant holder and into and through the lumen of the needle 56 attachedto the needle hub 58, thereby driving the implant out of the holder 84,through the needle, and ultimately out the distal end of the needle intothe external environment, such as, for example the anterior chamber of apatient's eye. Accordingly, the push rod 108, capable of being drivenforward by the spring 134, is the means for ejecting the implant fromthe apparatus following activation of the apparatus.

The choice of spring type and spring constant may be used to tune theejection force and ejection distance (the distance the implant isejected away from the tip of the needle upon activation of theapparatus). According to some embodiments, the present apparatus maycomprise a linear helical or a progressive helical spring. For example,the spring can be a coiled progressive compression spring as depicted inFIG. 25B. As can be appreciated, the force of ejection, whichcontributes to the distance the implant is ejected away from the tip ofthe needle (the ejection distance), will depend in part on the number ofactive or compressible coils, the “stiffness” of the spring, and thedegree to which the spring is compressed inside the housing prior toactivation. According to some embodiments the apparatus preferablyejects the intraocular implant a distance of 2-4 mm away from the tip ofthe needle in a liquid medium.

The spring-driven assembly (including the release lever and spring) iskept in a locked, ready-for-deployment position by the release lever dueto a flexible yet resilient tab 144 and its associated T-shapedprotuberance 145 located at the distal end of release lever 136, as seenin FIGS. 14A-14B. In the locked and ready position, prior to activationof the apparatus, the T-shaped protuberance 145 on tab 144 catches onthe two gate posts 147 positioned at the distal end of track 140 of thecover top 46. It can be seen in FIGS. 11A-11C that one gate post 147 ispositioned on each side of the track 140, much as sentries, to form anarrow gap through which the T-shaped protuberance 145 cannot pass.Thus, protuberance 145, being an integral part of release lever 136,holds release lever 136 in place, even under the rearward pressureemanating from a compressed spring 134 (spring 134 is compressed betweenthe proximal end of release lever 136 and the back stop (disk 149′) onknob shaft 74). From FIGS. 17A-17C and 20A-20B, it can be seen thatprotuberance 145 and thus tab 144 of the release lever is in contactwith the underside of ejector button 64 extending inside the housingthrough opening 66 in cover top 46. The energy stored in the compressedspring is released, and the spring-driven assembly is thereby translatedforward (i.e., along the length of the housing and toward the distal endof the apparatus) under pressure from the spring, when tab 144 onrelease lever 136 is forced down, out of its locked position, by manualdepression of ejector button 64. Tab 144 can be of a moldable plasticand integrally formed with the release lever.

It will be understood from the many views of the apparatus provided withthis description that the underside of the ejector button is alsooperably connected with push rod guide 118 and implant holder 84 by wayof the push rod assembly sleeve 120. The user transmits force to thesleeve through the underside of the button by manually depressing thebutton. As seen in FIGS. 2, 20A-20B, 21A-21B, and 24 , curved flanks (orwings) 124 present on the portion of the ejector button that extendsinside the housing are disposed between posts 122 and 122′. When ejectorbutton 64 is depressed, wings 124 on button 64 slide against posts 122that extend laterally from each side of the sleeve 120. In this way, thewings on ejector button 64 serve to nudge sleeve 120 forward, in adirection along the longitudinal axis of the housing, toward the distalend of the apparatus. Accordingly, force applied to ejector button 64 ina direction normal to the longitudinal axis of the housing by the useris converted into a longitudinal force (a force aligned with thelongitudinal axis of the housing) on sleeve 120 and, thereby, the pushrod guide 118 and, in turn, the implant holder 84, which is attached tothe distal end of guide 118. The longitudinal force on the sleeve andtherefore push rod guide causes the push rod guide to translate forwardalong the longitudinal axis of the housing and in a direction toward thedistal end of the apparatus. This forward motion of the push rod guide,in turn, causes the implant holder to translate forward against nipple62 inside needle hub 58. When forced against the membrane, nipple 62forces open membrane 106 affixed to the distal end of the implantholder, as, for example, by causing the membrane or sections of themembrane to fold back, providing for unimpeded passage of the implantfrom the lumen of the implant holder into the lumen of the needle 56.See FIGS. 7A-7B.

Thus, manual depression of the ejector button (activation of theapparatus) simultaneously opens the membrane and triggers ejection ofthe implant from the device.

The present apparatus provides a significant advantage in that the userhas no influence on the ejection force (and therefore ejection distance)of the implant. The user activates the ejection mechanism by depressingejection button 64 but does not control the force by which the push rodmoves through the implant holder or needle. This is entirely a functionof the spring type, and potentially, by dampening features, if any. Thedepression of the ejector button moves the implant holder 84 against thenipple 62 forcing open the membrane, which previously closedcommunication between the implant holder and the needle, andconcurrently forces the tab 144 on the release lever 136 down and theprotuberance 145 out of its locked position by pushing it over the posts147 that previously blocked its path. However, after this sequence iscomplete, the user no longer influences the moving parts. Once therelease lever is forced out of its locked position by depression ofbutton 64, the stored energy in spring 134 is released and transmittedto the push rod 108, causing the push rod 108 to move through theimplant holder 84 and the needle lumen with a force that is determinedentirely by the spring present inside the housing. The membrane alsoprevents the implant from prematurely falling out the distal end of theimplant holder during assembly, storage, and handling of the apparatus.

The movement of push rod 108 by spring 134 thereby forces the implantout of the holder 84, through the needle lumen, and eventually out ofthe needle and into the eye. The distance the implant is ejected awayfrom the tip of the needle and into the intracameral space of the eyecan, therefore, be pre-set by the spring set up (e.g., spring type,spring constant, and degree of compression). Additional rubber orplastic components may be optionally included inside the housing, ifdesired, to dampen the force generated by the spring, to fine tune theejection distance of the implant, or to further minimize the noiseassociated with the activation of the apparatus and ejection of theimplant. For example, rubber components can be added between the implantholder and the needle hub where contact may occur and where a “click”sound might be heard. Thus, the force applied to the ejector button isnot proportional to and does not influence the force by which theimplant is ejected. This design provides for consistent,user-independent performance, whereby the ejection force of the implantis a product of the internal spring-driven assembly of the apparatus andnot the user.

In addition, the activation path (the distance the ejector button musttravel to trigger ejection of the implant) in the present apparatus maybe shorter than some other implant delivery devices. For example, in thepresent apparatus the activation path can be about 1 mm to 2 mm, whereassome devices may require that the button be depressed by up to about 5mm or more before activation (actuation) takes place. The longer theactivation path the greater the possibility for shaking of the apparatusand, possibly, moving the tip of the needle while in the eye. Theshorter activation path of the present apparatus is expected to resultin a more comfortable and more controlled, less shaky implant deliveryprocedure for patient and doctor.

It is desirable to use a high gauge (e.g., 27 gauge to 30 gauge) needle.The distal end of the needle is preferably beveled to facilitatepenetration of the eye, such as the cornea, sclera, and vitreous cavity.Accordingly, the needle may correspond to a 27 gauge, 28 gauge, 29gauge, or 30 gauge needle. Smaller (higher gauge) needles are preferredfor injection into the eye to minimize trauma and fluid leakage. Theneedle may be cylindrical or non-cylindrical, and may therefore have acircular or non-circular cross-sectional area. In either form, theneedle is preferably able to receive a fiber-, filament-, tubular-, orrod-shaped intraocular implant within its lumen.

Because the present apparatus provides a means for rotating the needle,the bevel may be rotated clockwise or counter-clockwise to suit theuser's preference. Thus, the bevel may be oriented toward or away fromthe globe of the eye, depending on the needs or preference of the user.This enables the user to grasp the apparatus with either hand in themanner desired with fore-, index-, or ring-finger or thumb on theejector button and to then approach either the right or left eye at theangle necessary and with the bevel up or down or in any other desiredorientation to deliver the implant into the eye (including the anteriorchamber or vitreous body of the eye). See FIGS. 8A-8B, for example.

The means used to rotate the needle can be understood by reference toFIG. 4 . The needle is rotated using the needle (or bevel) rotation knob52 located at the proximal end of the housing 40. As can be seen inFIGS. 1A-3, 5A-5C, 6, 8A-8B, and 9A-9B, the knob itself (in associationwith the coding element 76) is beveled to match the needle bevel. Asdiscussed previously, the coding element is component that is attachedto the end of the needle-rotation knob that serves to indicate theposition of the needle bevel. It is a single moldable piece having afinger-like projection 75 that runs longitudinally along the surface ofthe knob and a beveled back surface 77 that attaches flush to theproximal end of the needle-rotation knob. Thus, when connected to thecoding element the needle-rotation knob has a beveled end similar to theneedle. The bevel of the knob and the finger-like projection 75 runninglengthwise along the outer surface of the knob are aligned with thebevel of the needle to clearly and unambiguously indicate theorientation of the needle bevel. A rubber or plastic material may bepositioned between the bevel rotation knob and the housing, or the knobmay be simply snugly fit to the housing to provide frictional resistanceto the rotation of the knob, securing the knob once the user has rotatedit to the desired location. Alternatively, or in addition, the top orbottom cover of the housing may be configured with a flexible tab, suchas tab 72 previously discussed, that tends to flex against a portion ofshaft 74 connected to knob 52 in the interior of the housing. Thisapplies a frictional force to the shaft 74 that resists free, unintendedmovement of the needle rotation knob 52 and thereby ensures that theneedle stays in position, initially selected by the user, during use ofthe apparatus.

As can be understood from FIGS. 2, 6, 9A-9B, and 25A-25B, knob 52 isoperably connected to metal connecting rod 148 inside the housing viashaft 74. Metal connecting rod 148 is fixedly mated with knob shaft 74inside the housing and to push rod guide 118. As can be understood fromFIGS. 2, 6, 21A-21B, and 25A-25B, metal rod 148 extends through thecenter of spring 134. Metal connecting rod 148 transmits the rotarymotion applied to knob 52 by the user into rotary motion of push rodguide 118 through to implant holder 84 and needle hub 58 at the distalend of the device. In this way, by twisting knob 52 the user can twistor rotate needle 56 and thereby orient the bevel of needle 56 relativeto the surface of the eye. Thus, needle-rotation knob 52 may also bereferred to as a bevel rotation knob

As previously discussed, the presently described intraocular implantdelivery apparatus may further include features such as implantinspection windows 112 and 112′ located in the nose cone 50 and needlehub 58, respectively, to facilitate visual or automated inspection ofthe intraocular or intracameral implant 68 in the device followingassembly, a delivery feedback window 86 to confirm successful activationof the apparatus, and rubberized grips 70 on the exterior of the housing(e.g., the cover bottom) along with a triangular shape or triangularrounded shape or grip to improve the handling, manipulation, and controlof the apparatus by the physician. See FIGS. 1A-5C and 17A-17C, as wellthe other figures accompanying this disclosure. In its final assembledform, the apparatus also includes a removable safety cap 44, fitted andlocked into place over the nose cone 50. The safety cap not only coversand guards the needle but also blocks depression of the ejector buttonduring shipping and handling. Safety cap is configured with a bendableTab 89 a that clicks into recesses (88 a-d, for example) located on nosecone 50, cover top 46, and cover bottom 48 and in doing so places aprojection 92 against a boss section 94 on ejector button 64 (FIGS.1A-1D, 5A-5C, and 17A-17C). This interaction prevents prematureactivation of the device by blocking the upward movement of boss 94,which, as evident from the configuration and see-saw pivot axis 95 ofejector button 64, (FIGS. 18A-18E and 20A-20B), must occur when theejector button is depressed. In one embodiment, the safety cap isremoved and the safety lock is freed, by rotating the cap and pullingthe cap from the apparatus.

As described above, the present apparatus is particularly well suitedfor delivering a rod-shaped intracameral implant into the anteriorchamber of a patient's eye. In other embodiment, the apparatus is usedin a method for introducing a rod-shaped biodegradable drug-containingimplant into an ocular region of the eye such as, for example, thesubconjunctival space, subtenon space, or vitreous body of the eye totreat a medical condition of the eye. The method can comprise the stepsof inserting the needle of the apparatus into the subconjunctival space,subtenon space, or vitreous body of an eye (for example, the patient'seye), ejecting the implant from the apparatus into the subconjunctivalspace, subtenon space, or vitreous body of the eye and removing theneedle from the eye. According to some embodiments, the apparatus isused to deliver two or more rod-shaped intraocular drug-containingimplants into the anterior chamber, subconjunctival space, subtenonspace, or vitreous body of the eye to treat a medical condition of theeye. The patient can be a human or non-human mammal in need of treatmentfor a medical condition of the eye (an ocular condition), such as forexample glaucoma or ocular hypertension. Delivery of an implant into theanterior chamber of the eye will generally comprise inserting the needlethrough clear cornea into the intracameral space (or anterior chamber).Once the needle is advanced to the desired position the ejector buttonis depressed.

Because the apparatus can comprise a 28 gauge or higher gauge needle,the procedure may be less traumatic than with larger gauge needles. Thelength of needle protruding from the stop or nose 80 on needle hub 58 isset to be optimal for insertion into the anterior chamber of the eye. Ingeneral, this length can be 4 mm to 8 mm, 4 mm to 7.5 mm, 4 mm to 6 mm,4 mm to 5 mm, about 5 mm, or about 7.5 mm, as measured from the tip 82of the needle to the nose 80 of the needle hub. The provision of stop 80on needle hub 58 reduces the risk of advancing a needle too far into theeye, removing uncertainty, and the user-independent spring-drivenejection mechanism safely and reliably delivers the implant into theanterior chamber with optimum force.

Because the push rod assembly is designed to drive the implant well awayfrom the tip of the needle and into the fluid-filled medium of theanterior chamber, it is expected that the present device may reduce theincidence of implants adhering to the end of the needle and thereby thechance that an implant is dragged out of the eye or becomes lodged inthe cornea when the needle is removed. Deposition of the implant in thecorneal endothelium may result in adverse complications. Intracameralimplants preferably separate from the needle tip immediately afterejection. The present device can provide for clean separation of theimplant from the device since the push rod may not only drive theimplant through the lumen of the needle but may also drive the implantaway from the needle tip, thereby dislodging any air bubbles formed atthe needle tip during discharge of the implant.

In one embodiment of the foregoing method, the intracameral implant isbiodegradable and is produced by an extrusion process. Extruded implantswill generally comprise a biodegradable polymer matrix and apharmaceutically active agent associated with the polymer matrix. Thepharmaceutically active agent can be a chemical compound, protein, orsubstance effective for treating a medical condition of the eye.Examples of pharmaceutically active agents include, but are not limitedto steroids, non-steroidal anti-inflammatory agents, alpha-2 adrenergicreceptor agonists, prostamides, tyrosine kinase inhibitors, VEGFinhibitors, cyclosporins (such as, for example, cyclosporin A), andproteins.

Non-limiting examples of steroids that may be effective for treating amedical condition of the eye include dexamethasone, beclomethasone,betamethasone, and triamcinolone, and pharmaceutically acceptable saltsthereof.

Non-limiting examples of non-steroidal anti-inflammatory agents that maybe effective for treating a medical condition of the eye includeaspirin, diclofenac, flurbiprofen, ibuprofen, ketorolac, naproxen, andsuprofen, and pharmaceutically acceptable salts thereof.

Non-limiting examples of alpha-2 adrenergic receptor agonists that maybe effective for treating a medical condition of the eye includebrimonidine freebase and brimonidine tartrate.

Prostamides are potent ocular hypotensive agents useful in the treatmentof a number of various ocular hypertensive conditions such as glaucoma,elevated intraocular pressure, and other ocular hypertensive episodes.They belong to an ever-expanding family of prostaglandin F_(2α), C-1amides. The biosynthesis and pharmacology of prostamides has beenextensively described (e.g., Woodward et al. (2004) “Bimatoprost: Anovel antiglaucoma agent” Cardiovascular Drug Reviews 22(2):103-120).For example, naturally occurring prostamides, such as prostamide F_(2α),are biosynthesized from anandamide by a pathway exclusively involvingCOX-2. COX-1 is not involved (e.g., Yu et al. (1997) “Synthesis ofprostaglandin E2 ethanolamide from anandamide by cyclooxygenase-2” J.Biol. Chem. 272(34):21181-21186). One prostamide that has foundwide-spread use in ocular therapy is bimatoprost (CAS Registry No.155206-00-1) (Patil et al., 2009, “Bimatoprost-a review” Expert OpinionPharmacother. 10(16):2759-2768). Like other prostamides, bimatoprostexhibits no meaningful interaction with prostaglandin (PG) sensitivereceptors (Schuster et al. (2000) “Synthetic modification ofprostaglandin F_(2α) indicates different structural determinants forbinding to the prostaglandin F receptor versus the prostaglandintransporter” Mol. Pharmacology 58:1511-1516). Nevertheless, bimatoprostis a potent ocular anti-hypertensive agent and is highly effective forreducing elevated intraocular pressure in patients with open angleglaucoma or ocular hypertension (Coleman et al. (2003) “A 3-MonthRandomized Controlled Trial of Bimatoprost (LUMIGAN®) versus CombinedTimolol/Dorzolamide (Cosopt®) in Patients with Glaucoma or OcularHypertension” Ophthalmology 110(12): 2362-8.) Biodegradable implantscomprising a prostamide such as bimatoprost for placement in an ocularregion of the eye are described in U.S. Pat. No. 7,799,336. In someembodiments, the active agent is homogeneously or substantiallyuniformly distributed throughout the biodegradable polymer matrix of theimplant or may be present in the core or a reservoir within the implantand surrounded by an outer biodegradable or non-biodegradable layer.

As used herein, a “protein” shall have its common meaning as known inthe art, and can refer to biological molecules consisting of one or morechains of amino acids. Proteins can perform a vast array of functionswithin living organisms, including catalyzing metabolic reactions,replicating DNA, responding to stimuli, transporting molecules from onelocation to another, and acting as signaling molecules, as when theybind to a cell surface receptor. Proteins may be linear, branched, orcircular and may be chemically synthesized or naturally or recombinantlyproduced. In some embodiments, therapeutic proteins may also includeproteins that are modified, such as PEGylated proteins, orpost-translationally modified proteins.

Non-limiting examples of proteins that may be effective for treating amedical condition of the eye include proteins that specifically bindvascular endothelial growth factor (VEGF). Proteins that specificallybind VEGF in the eye may be effective for inhibiting, blocking, orreducing VEGF activity in an eye. The protein that specifically bindsVEGF can be a monoclonal antibody, DARPin, or anticalin. Anti-VEGFproteins such as these may be effective for reducing, retarding, orinhibiting neovascularization in an eye and for treating maculardegeneration.

An intraocular implant, such as an intracameral implant, comprising apharmaceutically active agent, such as an anti-hypertensive agent, maybe effective for reducing intraocular pressure (TOP) in the eye of apatient suffering from glaucoma or ocular hypertension. For example, anintracameral implant can be placed in the anterior chamber of the eye todeliver a therapeutically effective dose of an IOP-lowering drug, suchas bimatoprost or other prostamide, for an extended period (e.g., 30days or more). The anterior chamber refers to the space inside the eyebetween the iris and the innermost corneal surface (endothelium).

While the implant delivery apparatus described in this disclosure isdesigned for introducing a solid, rod-shaped implant into the anteriorchamber of an eye of a human or non-human mammal (such as a dog, monkey,and the like), the apparatus in accordance with this disclosure may finduse in a method for introducing an intraocular implant into otherlocations (or ocular regions) in the eye. Thus, for example, it may bepossible to use the present apparatus in a method to deliver adrug-containing intraocular implant into the vitreous body,subconjunctival space, subTenon's space, or posterior chamber of theeye, which is the space inside the eye between the back of the iris andthe front face of the vitreous. The posterior chamber includes the spacebetween the lens and the ciliary processes, which produces the aqueoushumor that nourishes the cornea, iris, and lens and maintainsintraocular pressure. Referring to FIG. 29 , these and other ocularregions of the eye (200) are shown in cross-section. Particular regionsof the eye (200) include the cornea (202) and iris (204), which surroundthe anterior chamber (206). Behind the iris (204) is the posteriorchamber (208) and lens (210). Within the anterior chamber is theanterior chamber angle (212) and trabecular meshwork (214). Also shownare the corneal epithelium (218), sclera (216), vitreous (219), ciliaryzonules (220), and ciliary process (221). Also shown is the limbus(222), which is the transition zone about 1-2 mm wide, where the corneajoins the sclera and the bulbar conjunctiva attaches to the eyeball. Theposterior segment of the eye is the rear two-thirds of the eyeball(behind the lens), and includes the vitreous, the retina, and the opticnerve.

To administer an intraocular implant into an ocular region of the eye,such as the anterior chamber, using the intraocular implant deliveryapparatus according to the present disclosure, the user can grasp theapparatus 40 between the thumb and middle finger or between index andmiddle finger along rubber-coated surfaces 70, as shown in FIGS. 8A-8B,and position the apparatus near the desired point of entry into thepatient's eye. The device allows one to comfortably use either the thumbor index finger to depress the ejector button. Generally, the needle isinserted into the anterior chamber of an eye by inserting the needlethrough the cornea at a point just anterior to the limbus (orcorneo-scleral junction, where the cornea joins the sclera and thebulbar conjunctiva attaches to the eyeball). The needle is then advancedinto the eye to a length of about 4 mm, as measured from the tip 82 ofthe needle, and the tip of the needle is pointed or aimed toward theinferior anterior chamber angle. The ejector button is then depressed todeploy the implant. The patient typically will be under a topical orlocal anesthetic. The needle is then withdrawn. Preferably, theresultant puncture site can self-seal upon withdrawal of the needle.Best results may be achieved by orienting the bevel of the needle awayfrom the surface of the eye.

According to some embodiments, an apparatus in accordance with thisdisclosure is used to delivery an intracameral drug-containing,rod-shaped implant into the anterior chamber of an eye, such as a humaneye. Because of the extremely small cross-sectional diameters or areasof intracameral implants, the length of the implant may need to beproportionally larger to provide the desired therapeutic dosages of someactive agents. According to some embodiments, an intracameral implant isa cylindrical or non-cylindrical rod-shaped implant that is 0.5 mm to2.0 mm, 0.5 mm to 2.5 mm, or 0.5 mm to 2.7 mm in length and from 150 μmto 250 μm or 150 μm to 200 μm (±10 μm) in diameter or width. Accordingto some embodiments, the total weight of the intracameral implant is 20μg to 120 μg or 50 μg to 100 μg (±10 μg). Preferably, the implant doesnot interfere with a patient's vision or result in other undesirablecomplications in the eye following placement in the anterior chamber ofthe eye.

Various methods may be employed to make a biodegradable intracameralimplant suitable for delivery with the present apparatus. Useful methodsmay include hot-melt extrusion methods, compression methods, pelletpressing, solvent casting, print technology, hot embossing, softlithography molding methods, injection molding methods, heat pressmethods and the like. The biodegradable intracameral implant fordelivery with the present apparatus can be configured as a rod.According to some embodiments, cast films or sheets are ground intomicroparticles that are then extruded into a rod-shaped filament.Alternatively, polymers and drug are dry mixed and then hot-meltextruded into a rod-shaped filament having a diameter and cut to alength suitable for placement in the anterior chamber of the eye. Theintraocular implant may be sized and configured for delivery through a28 gauge, 29 gauge, or 30 gauge needle and for compatibility with theanterior chamber of the eye, whereby the implant can fit into theanterior chamber angle (212 in FIG. 29 ) without touching or rubbingagainst the corneal endothelium, which can cause inflammation in theeye.

Methods for making a biodegradable bimatoprost-containing intraocularimplant by an extrusion process are familiar to those of skill in theart. See, for example, US 2008/0145403 and US 2005/0244464, which areherein incorporated by reference. An extruded implant (e.g., an extrudedrod) can be made by a single or double extrusion method. The use ofextrusion methods may allow for large-scale manufacture of implants andmay result in implants with a homogeneous dispersion of the drug withinthe polymer matrix. These processes may be adapted for use in makingother prostamide-containing intraocular implants.

In manufacturing an implant delivery device according to the invention,the device may be pre-loaded with the implant and then sterilized,adding convenience for the user and avoiding unnecessary handling ofimplants. A suitable dose of radiation for sterilization may be from 20kGy to 30 kGy.

In manufacturing the present intracameral implant delivery apparatus,needle rotation assembly 78, the spring-driven assembly, and push rodassembly 114 can be pre-assembled separately and the individualassemblies then interconnected. It may be appreciated that several ofthe components may be formed of moldable plastic configured the featuresdescribed herein. Push rod 108 and metal connecting rod 148 can be metalor a metal alloy. Alternatively, in some embodiments, the push rod orconnecting rod or both can be formed from a plastic or non-metallicmaterial.

When interconnected, the three assemblies align along the longitudinalor long axis of the housing as depicted in FIGS. 9A-9B, 24, and 25A-25B.As can be understood from FIGS. 6 and 25A-25B, and the several otherfigures accompanying this description, metal connecting rod 148 extendsthrough spring 134, release lever 136, and push rod assembly sleeve 120and fixedly interconnects to the proximal end of push rod guide 118. Theinterconnected assemblies, including the sleeve, can be interconnectedthen be enclosed within the housing formed initially by attachment ofcover top 46 (containing ejector button 64 extending through opening 66)to cover bottom 48. Nose cone 50 is attached at a later step, asdescribed below. As will be understood by reference to FIGS. 2, 10A-10C,11A-11C, 17A-17C, 20A-20B, and 21A-21B, ribs 156 on the interior ofcover bottom 48 and cover top 46 at the proximal end of the cover bottomand top come into contact with disk 149′ on knob shaft 74, blockingbackward movement of the shaft 74 (toward the proximal end of theapparatus). This blocks rearward movement and escape of those members(e.g., push rod guide and implant holder) fixedly secured to the shaftby the metal connecting rod 148. This fixes in place within the housingthe knob shaft, the metal connecting rod, and the push rod guide. Theblocked rearward movement is important since the knob shaft ultimatelyserves as the backstop to the spring, which when compressed placespressure against the knob shaft 74. See FIGS. 2, 17A-17C, 20A-20B, and24 . The ribs 156 in the housing cover top and bottom hold the shaft inplace during compression of the spring in the assembly process.

In a separate process, an intraocular implant (e.g., a rod-shaped,biodegradable, intracameral implant) can be pre-loaded in implant holder84 having membrane 106 affixed to its distal end. Membrane 106 can, forexample, be heat sealed onto the distal end of the implant holder andthe implant can be inserted into the implant holder. The implant holder84 can then be fixedly attached to the snap hooks 130 at the distal endof plunger guide 118. At this step, push rod 108 is received in thelumen of implant holder 84 where it will serve as a back stop to theimplant prior to deployment in the eye. Loss of the implant is preventedat this stage by the presence of the membrane 106.

Before attaching the nose cone to the cover top and bottom (46 and 48)and before the implant holder and push rod guide are connected to themetal connecting rod 148 inside the housing, the spring is “cocked” intothe compressed and ready-for-activation position by pushing the releaselever back toward the proximal end of the housing. This can be done, forexample, by inserting a solid cylindrical rod into the uncapped, opendistal end of the apparatus distal and then pushing the release leverback against the spring. In doing so, the user will usually hear anaudible click when the T-shaped protuberance 145 on release lever tab144 flips over the gate posts 147 present at the distal end of track 140on the underside of cover top 46. At this point the spring drivenmechanism is locked and ready for activation.

Next, the push rod guide 118 in association with the push rod 108,conveyor 116, and implant holder 84 is inserted through the uncappeddistal end of the apparatus to connect the guide 118 with the metalconnecting rod 148. Next, nose cone 50 containing needle hub assembly 54is snapped onto the proximal ends of cover top 46 and cover bottom 48.Finally, safety cap 44 is secured into place over nose cone 50 tocomplete the assembly. The apparatus can then be packaged andsterilized.

As can be appreciated, label plates or other locations on the housingcan include appropriate information relative to the particular implantloaded (e.g., drug, dosage, implant composition, and the like). Giventhis interchangeability, unique apparatus for the delivery of selectedimplants can be easily manufactured.

Accordingly, the assembly of the intraocular implant delivery apparatusaccording to this disclosure is straight forward and may be amenable toautomation. Because the implant holder with implant is a separate,self-contained unit that is attached to the assembly in one quick stepwithout the need for extra steps or parts, such as needle notching,crimping, or use of sleeves, O-rings, or plugs to prevent implant lossduring assembly as may be necessary in delivery devices in which theimplant is stored in the lumen of the needle or in a passageway justproximal to the lumen, the cost of assembly may be reduced and theefficiency of assembly increased relative to some other devices in whichthe implant must be retained in the lumen of the needle or cannula priorto use.

1. An apparatus for injecting an intraocular implant into the anteriorchamber of a patient's eye, the apparatus comprising: (a) an elongatehousing having a longitudinal axis and having a proximal end and adistal end; (b) an ejector button extending through an opening in thehousing and moveable from a first position to a second position in adirection normal to the longitudinal axis of the housing; (c) a needlehaving a proximal end and a distal beveled end, the needle extendinglongitudinally from the distal end of the housing, the needle having alumen extending through the length of the needle such that anintraocular implant can be received within and translated through thelumen of the needle, the needle rotatable in clockwise andcounter-clockwise directions about its long axis; and (d) an implantholder having a proximal and a distal end and a lumen capable ofreceiving and holding an intraocular implant prior to activation of theapparatus, the implant holder located inside the housing, the implantholder further being capable of movement, upon activation of theapparatus, from a first position to a second position within the housingalong the longitudinal axis of the housing and in a direction toward thedistal end of the apparatus, the lumen of the implant holder alignedwith the lumen of the needle such that an implant can slidably translatefrom the lumen of the implant holder into the lumen of the needle uponactivation of the device, the implant holder capped at its distal endwith a cross-slit membrane, wherein depression of the ejector buttonresults in activation of the apparatus and ejection of the implant fromthe apparatus.
 2. The apparatus of claim 1, further comprising anintraocular implant, the implant located entirely within the implantholder, wherein the intraocular implant is a solid, rod-shaped,biodegradable, intraocular implant comprising a biodegradable polymermatrix and a pharmaceutically active agent associated with thebiodegradable polymer matrix, wherein the pharmaceutically active agentis effective for treating a medical condition of the eye, and whereinthe implant is 150 μm to 300 μm in diameter or width, 0.50 mm to 2.5 mmin length, and 20 μg to 120 μg in total weight.
 3. The apparatus ofclaim 2, wherein the length of the needle extending from the distal endof the housing is 4 mm to 8 mm.
 4. The apparatus of claim 1, furthercomprising a push rod having a proximal and a distal end, wherein priorto activation of the apparatus the distal end of the push rod isdisposed in the lumen of the implant holder at the proximal end of theimplant holder, and wherein the push rod is slidably receivable withinthe lumen of the implant holder and the lumen of the needle, and whereinthe push rod is moveable along the longitudinal axis of the housing. 5.The apparatus of claim 4, further comprising a spring-driven assemblyengageable with the push rod for forcing the push rod through theimplant holder and the lumen of the needle following activation of theapparatus.
 6. The apparatus of claim 1 further comprising aneedle-rotation knob located at the proximal end of the housing, wherebymanual rotation of said knob in a clockwise or counter-clockwisedirection relative to the longitudinal axis of the housing results in acorresponding clockwise or counter-clockwise rotation of the needle. 7.The apparatus of claim 1 further comprising implant inspection windowslocated on the distal end of the housing, wherein said implantinspection windows are configured to permit visual observation of animplant inside the housing prior to activation of the apparatus.
 8. Theapparatus of claim 1, further comprising an implant delivery feedbackwindow located on the housing, wherein said feedback window isconfigured to allow observation of a visible signal that indicatesactivation of the apparatus.
 9. The apparatus of claim 1, wherein saidneedle is a 28 gauge needle with a wall that is 0.0015 inches to 0.00225inches thick.
 10. The apparatus of claim 2, wherein the pharmaceuticallyactive agent is a steroid, a non-steroidal anti-inflammatory agent, analpha 2 adrenergic receptor agonist, a prostamide, or a protein.
 11. Amethod of introducing an intraocular implant into the anterior chamberof a patient's eye, the method comprising: (a) penetrating the cornea ofa patient's eye with a distal beveled end of a needle extending along alongitudinal axis from a distal end of an elongate housing of anintraocular implant delivery apparatus, the needle rotatable in aclockwise direction and a counter-clockwise direction about thelongitudinal axis; (c) inserting the needle into the anterior chamber ofthe patient's eye; (d) ejecting the intraocular implant from theapparatus using an ejector button extending through an opening in theelongate housing into the anterior chamber of the patient's eye; and (e)removing the needle from the patient's eye.
 12. The method of claim 11,wherein the penetrating step comprises inserting the needle into thecornea with a bevel of the needle oriented 180° away from a cornealsurface of the eye.
 13. The method of claim 12, wherein the needle isinserted into the anterior chamber by inserting the needle through thecornea at a point just anterior to the limbus.
 14. The method of claim11, wherein needle is inserted into the anterior chamber to a depth ofabout 4 mm to about 7.5 mm, as measured from a tip of the needle to thecorneal surface where the needle first penetrates the eye, and whereinthe needle is pointed toward the inferior anterior chamber angle beforeejecting the implant.
 15. The method of claim 11, wherein the patienthas glaucoma or ocular hypertension.
 16. An apparatus for injecting anintraocular implant into the anterior chamber of a patient's eye, theapparatus comprising: (a) an elongate housing having a longitudinalaxis, a distal end of the elongate housing comprising implant inspectionwindows configured to permit visual observation of an implant within theelongate housing prior to activation of the apparatus; (b) a needleextending longitudinally from the distal end of the housing, the needlehaving a distal beveled end and a lumen extending through the length ofthe needle such that an intraocular implant can be received within andtranslated through the lumen of the needle toward the distal beveledend; (c) an implant holder located inside the elongate housing andhaving a lumen capable of receiving and holding the intraocular implantprior to activation of the apparatus; and (d) an ejector buttonextending through an opening in the elongate housing and moveable from afirst position to a second position to activate the apparatus to deliverthe intraocular implant through the lumen of the needle.
 17. Theapparatus of claim 16, wherein the implant holder is made of atransparent material such that the intraocular implant can be visualizedthrough the implant inspection windows and the implant holder prior toactivation of the apparatus.
 18. The apparatus of claim 16, wherein theimplant holder comprises implant inspection windows, wherein alignmentof the implant inspection windows of the implant holder with the implantinspection windows of the elongate housing permits visual observation ofthe intraocular implant within the apparatus prior to activation of theapparatus.
 19. The apparatus of claim 18, wherein the implant inspectionwindows of the elongate housing comprises two windows on a nose cone ofthe elongate housing separated from one another by about 180 degrees,and wherein the implant inspection windows of the implant holdercomprises two windows on a needle hub of the implant holder locatedinside the nose cone and separated from one another by about 180degrees.
 20. The apparatus of claim 16, wherein at least one of theinspection windows of the elongate housing is a magnifying element thatmagnifies a view of the implant inside the implant holder.